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To be or not to be: navigating the influence of MicroRNAs on cervical cancer cell death
Cancer Cell International volume 25, Article number: 153 (2025)
Abstract
With all diagnostic and therapeutic advances, such as surgery, radiation- and chemo-therapy, cervical cancer (CC) is still ranked fourth among the most frequent cancers in women globally. New biomarkers and therapeutic targets are warranted to be discovered for the early detection, treatment, and prognosis of CC. As component of the non-coding RNA’s family, microRNAs (miRNAs) participate in several cellular functions such as cell proliferation, gene expression, many signaling cascades, apoptosis, angiogenesis, etc. MiRNAs can suppress or induce programmed cell death (PCD) pathways by altering their regulatory genes. Besides, abnormal expression of miRNAs weakens or promotes various signaling pathways associated with PCD, resulting in the development of human diseases such as CC. For that reason, understanding the effects that miRNAs exert on the various modes of tumor PCD, and evaluating the potential of miRNAs to serve as targets for induction of cell death and reappearance of chemotherapy. The current study aims to define the effect that miRNAs exert on cell apoptosis, autophagy, pyroptosis, ferroptosis, and anoikis in cervical cancer to investigate possible targets for cervical cancer therapy. Manipulating the PCD pathways by miRNAs could be considered a primary therapeutic strategy for cervical cancer.
Introduction
Cervical cancer (CC), a frequent female malignancy, possesses a high rate of mortality worldwide and is considered a major global health challenge [1, 2]. Adenocarcinoma and squamous cell carcinoma, respectively generate 25% and 70% of all CCs and are the most common histological subtypes [3, 4]. Several factors and genes are implicated in generating the molecular regulatory mechanism of CC [5, 6].
Additionally, high-risk subtypes of the human papillomavirus (HPV) are known to be responsible for most CCs. Considering the major contribution of this virus, HPV screening and vaccination programs are identified as effective strategies in the prevention of CC [7]. In the context of treatment, it should be noted that surgical resection is still the foremost treatment option for early-stage CCs due to its acceptable prognosis [5, 6]. However, the diagnosis and treatment platform for CC are not specified for monitoring the prognosis, tumor metastasis, and recurrence, thereby lacking individualized treatment.
Through eliminating damaged cells, cell death takes a fundamental role in the maintenance of physiological homeostasis and can appear as an aberrant pathological response to damaging stimuli [8, 9]. In accordance with morphology, biochemistry, and function, cell death modes are divided into accidental cell death and regulated cell death (RCD) [10]. As the name suggests, accidental cell death is an uncontrolled biological process in reaction to accidental injury stimuli [11]. Despite this, RCD is characterized by regulated signaling cascades with critical roles in the development of organisms or tissue renewal [12]. Malignant cells, however, are capable of evading the RCD routes through various mechanisms [13]. RCD pathways are pivotal for cancer immune surveillance, progression, metastasis, and the prognosis of patients [14, 15]. Different forms of RCD could alter the tumor microenvironment through the release of pathogen- or damage-associated molecular patterns (PAMPs or DAMPs), which impacts anti-cancer therapy [16,17,18]. Therefore, more investigations are a must for a more comprehensive understanding of the implication of cell death pathways in cancer therapy and development.
MiRNAs are small, non-coding RNAs capable of binding to the target mRNAs and, altering the translation of the target proteins, or even degrading the mRNA [19,20,21]. Various cellular processes, like metabolism, proliferation, and cell death, in distinct types of cells are modulated by miRNAs [19, 22, 23]. Abnormal expression of miRNAs weakens or modifies various RCD, leading to human cancer development. As well, several miRNAs are identified to alter the expression of RCD genes [24, 25]. Aberrations involving miRNAs involved in apoptosis, autophagy, pyroptosis, ferroptosis, anoikis, and necroptosis can also influence the physiological conditions and affect carcinogenesis. The present study contains a review of the significant role of miRNAs in controlling the critical cell death pathways, namely, apoptosis, autophagy, pyroptosis, anoikis and ferroptosis of cervical cancer cells.
MicroRNA biogenesis
During canonical biogenesis, RNA polymerase II transcribes miRNAs and produces a double-stranded hairpin primary (pri)-miRNA transcript, which are further cleaved into a short hairpin structure known as pre-miRNA. After translocation of pre-miRNA to the cytoplasm, their terminal loop gets removed by the RNase III endonuclease Dicer and leaves a mature miRNA duplex strands [26]. Either strand of mature miRNA (− 5p or − 3p) can be loaded onto the Argonaute protein to generate the RNA-induced silencing complex (RISC). The strand with more thermodynamical stability will be proportioned in RISC while the less stable strand will be degraded [27]. The proportion of strands can also be equal or dependent on the cell type. Besides, according to the functionality of proportion of the strands (− 5p or − 3p), RISC could be directed towards divergent gene targets [28, 29]. Next, through attaching to the 3’-UTR of target mRNA, miRNAs affect gene expression, either by translational repression or even degradation, resulting in the regulation of various cellular processes and disease progression. Moreover, both miRNAs and pre-miRNAs are stable in extracellular environment and can be released into the bloodstream in free form or in exosomes, microvesicles, high-density lipoproteins or protein complexes, where they are adsorbed by cell-to-cell communication [30]. Therefore, they are considered therapeutic targets and clinical biomarkers for individualized therapy in complex diseases [31,32,33,34,35].
Apoptotic and anti-apoptotic MicroRNAs in cervical Cancer
Among the different types of RCD, apoptosis and autophagy are the most pivotal ones with the ability to promote organelle degradation or stress-induced cell death and serve a critical role in targeted therapy as well as regulating cancer cell death [36]. Apoptosis is identified as a crucial intracellular process for maintaining organism homeostasis and controlling cell populations. Various morphological features of apoptosis such as shrinkage of cell, condensation of chromatin, blebbing of the membrane, DNA fragmentation, and the formation of apoptotic bodies [37,38,39].
Depending on the activation, apoptosis is categorized into two modes; intrinsic and extrinsic pathways. The intrinsic pathway activates once stressed cells produce an internal signal and relies on the cytoplasmic release of cytochrome C into the mitochondrial intermembrane space (MIS), through the mitochondrial outer membrane (MOM) pores. BCL-2 family proteins are the main regulators and effectors of the permeabilization of MOM, resulting in the release of cytochrome C from the MIS [40]. BCL-2 family members are categorized as effectors (including BAX and BAK), the pro-apoptotic BH3-only (e.g., Bad, Bid, Bik, and Bim) and anti-apoptotic proteins (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1) [40, 41]. Through the release of cytochrome C from MOM into the cytosol, BCL-2 members trigger the activation of caspase cascade, leading to apoptosis [42]. In the extrinsic pathway, on the other hand, the activation of receptors through members of the tumor necrosis factor (TNF) receptors (e.g., FAS) and TNF-related apoptosis inducing ligand (TRAIL) receptors, is required. Binding of death ligands (TNFα, FAS, and TRAIL) to their receptors activates the extrinsic pathway and further result in recruitment of caspase9/10 and, thereby the formation of a death-inducing signaling complex (DISC) [42]. Afterward caspase9/10 activated by autocleavage in the DISC, triggers the activation of downstream executioner caspases (caspase3/6/7) (Fig. 1) [43, 44].
Cancer cell apoptosis and regulatory non-coding RNAs. Regulatory microRNAs are highlighted in orange
Caspases, a group of proteases, are mostly identified by their role in PCD (mostly apoptosis and pyroptosis), and the inflammatory cascade. Caspase3/6/7/8/9 in mammals are known as apoptotic caspases, whereas caspase1/4/5/12 in humans and caspase1/11/12 in mice are considered as inflammatory caspases [45]. Furthermore, apoptotic caspases are classified into initiator caspases (caspase-8/9) and executioner caspases (caspase3/6/7) based on their mechanism of action [46,47,48].
All, PCD pathways such as apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis appear to get regulated by various miRNAs. In that regard, within the next section, we summarize the mechanism of inhibiting or inducing apoptosis in cervical cancer by cellular miRNAs.
Apoptotic MicroRNAs in cervical cancer
In critical biological and pathological processes, miRNAs are found to be crucial regulators [19, 21, 45, 46]. Considering the pivotal part of miRNAs in the regulatory network, any changes in their expression are correlated with tumor progression. In that context, many researches have been centered on the participation of miRNAs to the carcinogenesis and progression of CC [47,48,49,50]. For instance, the role of miR-218 as an apoptosis regulator and suppressor of progression has been investigated in CC [51,52,53]. Yu et al. [54] reported that the expression level of survivin and miR-218 are downregulated and upregulated, respectively, in cisplatin (DDP)-resistant HeLa/DDP and SiHa/DDP cells in contrast to the mock HeLa and SiHa cells. In return, enforced expression of miR-218 elevates the cisplatin sensitivity of CC cells by promoting apoptosis. As well, induction of miR-218 is found to promote apoptosis in CC cells’ resistance to DDP by targeting survivin [54]. In that regard, Yuan et al. [55] found that enforcing the expression of miR-218 elevated the radiosensitivity in CC cells, including HeLa, SiHa, C33A, and CaSki cells by promoting apoptosis [55]. Similarly, another study demonstrated that miR-218 increases chemosensitivity to DDP in Hela cells via promoting CC cell apoptosis [56]. Zhu et al. observed that miR-218 overexpression suppresses cell viability and elevates apoptosis in CC cells via the JAK2/STAT3 pathway [57]. GLI3, in the GLI family, affects proliferation and apoptosis in cancer cells [58,59,60]. Recently, it has been observed that Gli3 mRNA and protein expression are inversely associated with levels of miR-218 in CC tissues [61]. In addition, miR-218 is found as a suppressor of CC cells proliferation, apoptosis, and cell cycle progression of through downregulating Gli3. It also has been established that transfection of miR-218 mimics in CC cells results in promoted apoptosis and enhanced caspase-3 activity [61]. These results suggested that miR-218 can suppress cell growth and regulate tumor progression through elevating the activity of caspase-3 and inducing apoptosis in CC cells.
The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) cascade, is a critical signaling cascade which involved in regulating apoptosis, and blocks the expression of pro-apoptotic proteins, suppresses tissue apoptosis, and elevates the survival rate of cancerous cells [62]. Focal adhesion kinase (FAK) is a signaling molecule identified to activate PI3K [63, 64]. In fact, FAK participates in the cell survival regulation and protection from apoptosis [65,66,67]. It has also been established that FAK suppresses cell apoptosis through triggering the PI3K/Akt cascade [68, 69]. Phosphorylation of FAK occurs upon stimulation and enables it to attach to the p85 subunit of PI3K and consequently triggers the PI3K/Akt signal cascade. Furthermore, activation of FAK-PI3K/Akt pathway participates in the protection of cancer cells from oxidative stress-induced apoptosis through promoting nuclear factor-κB (NF-κB) to mediate the expression of caspase inhibitors of IAPs [66]. Similar to FAK, MTDH serves a crucial role in various biological processes in tumorigenesis and development through integrating oncogenic cascades, such as PI3K/AKT, NF-κB, mitogen-activated protein kinase (MAPK), and Wnt/β-catenin [70, 71]. Overexpression of MTDH suppresses apoptosis, and in return, downregulation of MTDH is able to reduce tumor cell growth, and promote apoptosis [72, 73]. In CC, MTDH is overexpressed and has a remarkable association with tumor size, lymph node metastasis, TNM stage, and tumor differentiation [74, 75]. Liang et al. [76] found that upregulated miR-433 induces CC apoptosis and suppresses proliferation and invasion by targeting MTDH. Additionally, upregulated MTDH mRNA expression in CC tissues has an inverse association with miR-433 expression. Overexpression of MTDH is able to reverse the influence of upregulated miR-433 in regard to proliferation, invasion, and apoptosis of CC cells. Moreover, miR-433 is found to inactivate AKT and β-catenin pathways in CC via targeting MTDH [76]. Collectively, these data indicate that miR-433 suppressed the growth of CC cells via the promoting apoptosis pathway by modulating the FAK-MTDH/PI3K/AKT signaling cascade.
Furthermore, BCL-2 protein is found to inhibit apoptosis through the formation of a heterodimer with BAX and guarantee cell survival by controlling the Ca2t concentration and antioxidant effect [77]. BCL-2 is also able to suppress the activities of caspase-9/3/6/7 [78], in order to eliminate apoptosis, elongate the survival time of tumor cells, and create malignant cell transformation [79]. Recent evidence supports that miRNAs act as tumor suppressor factors in CC through promoting apoptosis pathways via targeting Bcl-2 (Table 1). For example, Chen and colleagues [84] found that miR-744 negatively regulates Bcl-2 and subsequently suppresses CC growth and progression through promoting apoptosis [80]. Enforced miR-211 expression, on the other hand, promotes apoptosis in CC cells (SiHa cells) by targeting Bcl-2 and upregulating apoptotic proteins, such as caspase-3, and PARP [81]. Similarly, He et al. [82] reported that miR-187 promotes apoptosis of SiHa CC cells by suppressing the expression of Bcl-2 [82]. Moreover, miR-636 is found to be downregulated in CC tissues and cell lines. Overexpression of miR-636 results in suppressed cell proliferation and elevated cell apoptosis. Knockdown of miR-636, on the other hand, is capable of reversing these effects on CC tumorigenesis. In addition to Bcl-2, mir-636 is found to target cyclin-dependent kinase 6 (CDK6) and upregulation of CDK6 or Bcl-2 might reverse the inhibitory effect of miR-636 on the progression of CC. Therefore, CDK6/Bcl-2 are considered targets of miR-636 for promoting CC cell [83]. Bcl2l2 (also known as Bcl-w), was initially classified among BCL-2 family proteins, and it’s overexpression was found to shield lymphoid and myeloid cells from cytokine deprivation and γ-irradiation-induced apoptosis [84].
Through apoptosis protection of cells and promotion of cell survival, Bcl2l2 participates in chemoresistance [84,85,86,87]. In fact, Bcl2l2 is overexpressed in various cancer types to promote their carcinogenesis, for instance, non-small cell lung cancer [88], gastric and colon cancers [89, 90]. Wang et al. [91] established that upregulated Bcl2l2 in CC tissues promotes cell survival and cisplatin resistance. Furthermore, they confirmed that through the direct attachment of miR-214 to the 3ˊ UTR of Bcl2l2 mRNA, it can suppress Bcl2l2 at the post-transcriptional level. Moreover, they suggested that enforced expression of miR-214 in HeLa cells could upregulate Bax as well as caspase-9/8/3, which were partly reversed through upregulation of Bcl2l2. This indicates that both extrinsic and intrinsic pathways are implicated in miR-214-induced apoptosis [91].
With a similar structure to the BCL-2 gene, the BCL-XL, is a MOM and nuclear membrane protein capable of binding to nuclear proteins and regulating the activity of transcription factors [31]. BCL-XL has higher expression in tumor cells in contrast to standard cells, and is associated with the proliferation, growth, metastasis, apoptosis resistance and maintenance of stem cell phenotypic of tumor cells [92, 93]. A high expression level of Bcl-xL has been reported in CC cells (c-33a cells) and miR-421-transfected c-33a cells exhibit reduced Bcl-xL expression, suppressed growth, promoted apoptosis, and activated caspase-3. In addition, among BCL2 family members, MCL1 inhibits the apoptosis pathway through the inhibition of BAX and BAK activation [94]. It has been demonstrated that miR-320 induces HeLa cell apoptosis by negatively and positively regulating Mcl-1 and caspase-3, respectively (Fig. 1) [95]. Overall, because apoptosis suppression is pivotal in cancer development and constitutes a main barrier for effective therapy, the research on miRNAs targeting multiple Bcl-2 family members could serve as a promising target for CC treatment.
Radiation triggers the activation of several survival and death signaling molecules, mainly implicated in the retraining of the cell cycle, the repair of DNA damage, and apoptosis induced by stress responses. A result, the remaining viable cells become radio-resistant [96, 97] and will proliferate and grow in order to spread to secondary sites, subsequently resulting in organ failure. Recently, the involvement of miRNAs in promoting radiosensitivity by enhancing apoptosis has been the center of efforts [98] which suggests them as promising therapeutic targets for radioresistant tumor progression.
The family of miR-29, comprises three members, namely miR-29a, -29b, and − 29c, is capable of precipitating in the carcinogenesis and malignant transformation of various cancers [99,100,101]. However, the mechanism of miR-29 contribution to the elevation of radio-resistance in CC is yet not clarified. Downregulation of miR-29a is found in radioresistant CC cells (RR-CaSki cells). In fact, miR-29a could serve as a critical tumor suppressor, and it can restrict the malignant transformation process in CC cells [102]. Enforced miR-18a expression in CC cell radio-resistance including SiHa and HeLa cells, leads to re-sensitizing the CC cells to radiotherapy by enhancing apoptosis through targeting ATM, a key protein in DNA damage response. Upregulated miR-218 enhances the radiation-induced apoptosis in CC cells [102]. Furthermore, miR-145 is established to promote apoptosis-induced radiotherapy in CC cells. Taken together, these data suggest miRNAs as promising candidates implicated in augmenting radiosensitivity and escalating the apoptotic effect to alleviate the radio-resistance of CC cells.
Outnumbered research has established miR-143 as a tumor suppressor that is downregulated in many malignancies, such as CC [103,104,105,106]. Downregulation of miRNA-143 is in fact associated with tumor size and lymph node metastasis of CC [107]. Besides, miRNA-143 participates in the chemosensitivity of several malignancies and its overexpression is found to suppress CC progression and restrict migratory and invasive activity [103, 108, 109]. Recently, Esfandyari et al. [110] confirmed that miR-143 could enhance cisplatin-induced apoptosis and the sensitivity of CaSki cells to lower doses through altering the expression of apoptosis-related genes including Bcl-2, Bax, and caspase-9 [110]. As eluded in Fig. 1, miR-143 can also stimulate CC cell apoptosis through inhibiting HIF-1α, which can protect CC cells from irradiation-induced apoptosis through downregulating p53 [111]. In this regard, Zhao et al. [112] established that ectopic expression of miR-143 could enhance CC cell apoptosis by negatively regulating HIF-1α [112]. Also, upregulation of miR-143 is found to inhibit HeLa cell proliferation and elevate apoptosis. Furthermore, Bcl-2 is targeted by miR-143 [105], resulting in elevated apoptosis rate in CC cells (SiHa and HeLa cells) [113]. Besides, upregulation of miR-143 expression is shown to reduce Bcl-2 expression while increasing Bax expression in HeLa cells following 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) [114]. As well, the downregulation of miR-143 expression suppresses the influence of ALA-PDT on Bcl-2/Bax protein expression [115]. In conclusion, upregulated miR-143 mediated by the ALAPDT method results in the induction of cervical cancer cell apoptosis by negatively and positively regulating Bcl-2 and Bax levels.
Anti-apoptotic MicroRNAs in cervical cancer
Among miRNAs with the ability to regulate apoptosis, many are identified as anti-apoptotic in CC. This distinction relies on experimental results from a particular cell type. As far as we know and according to the available literature, 28 miRNAs have been shown to inhibit apoptosis, suggesting they may be onco-miRs in CC (Table 2). For example, miR-146a, -766-5p, -205-3p, -501, -378, -543, -574-5p, -141-5p, and − 15a-5p levels were found to be upregulated in CC tissues and also elevate the apoptosis of CC cell lines by directly targeting TRAF6 [116], SCAI [117], DDI2 [118], CYLD [119], ST7L [120], BRIP1 [121], QKI [122], BTG1 [123], and TP53INP1 [124], respectively. Interestingly, some miRNAs including miR-22, -425, -204, -130b-5p, -338-3p, -181, and − 543 have been found to either promote or inhibit the apoptosis of CC cell, suggesting its dual function in cancer progression, which will be briefly discussed below.
Among the THBS protein family, thrombospondin-2 (THBS2) is an extracellular matrix (ECM) protein that can regulate cell migration, apoptosis, and cytoskeleton after secretion from stromal fibroblasts, endothelial cells, and immune cells. HBS2 could suppress angiogenesis through controlling matrix metalloproteinases (MMPs) and ECM proteins [13]. MiR-1246/THBS2/ECM signaling pathways seem to be implicated in CC metastasis. Depending on the cancer type, the level of THBS2 expression varies, and in CC [125], gastric cancer [126], and ovarian cancer [127], it appears to be downregulated. At the same time, it appears to be overexpressed in pulmonary adenocarcinoma [128], and prostate cancer [129], suggesting that THBS2 could serve other pro-tumoral functions. Therefore, a controversial role could be described for THBS2 in tumorigenesis. Recently, Zhou and colleagues [130] found that THBS2 and miR-20a expression are notably reduced and increased, respectively, in CC tissues and cells and have an inverse association with miR-20a expression in CC tissues. Moreover, inhibition of miR-20a leads to suppressed proliferation, elevated apoptosis, and mitigated autophagy in CC cells [130]. Altogether demonstrated that suppressed proliferation, autophagic activity, and promoted apoptosis are due to the downregulation of miR-20a which targets THBS2 in CC cells. These sheds light on the implication of miR-20a in CC development.
As eluded in Fig. 1, miR-1246 is able to suppress CC apoptosis through the THBS2/MMP signaling pathway. Downregulation of MMP2/9 levels and upregulation of the ECM are after miR-1246 knockdown, indicates THBS2/MMP/ECM axis as a pathway for this miRNA to regulate CC cell pathogenesis [131]. In addition, miR-181a, as one of the members of the miR-181 family, inhibits CC cell apoptosis through negatively regulating the PTEN/Akt/FOXO1 axis [132].
As can be seen in Table 2, miR-181a and − 181b are overexpressed in CC tissues. Functionally, it has also been observed that miR-181b contributes to the progression of CC via suppressing apoptosis and promoting cell proliferation through downregulating adenylyl cyclase 9 (AC9) in CC cells [133]. Overexpression of protein kinase C delta (PRKCD) can be targeted by miR-181a to stimulate the apoptosis resistance of CC in response to radiation therapy [134]. In fact, PRKCD appears to be critical to mounting an apoptotic response under stress conditions [135, 136]. Therefore, negative regulation of PRKCD by miR-181a mediates radio-resistance through enhancing cancer cell apoptosis [137]. Thus, targeting miR-181a could be a novel approach to sensitizing CC to radiation therapy. The tumor suppressor gene Phosphatase and tensin homolog (PTEN) encodes dual-specificity phosphatase [138] and comes second among frequently mutated genes in cancers after P53, thereby its inactivation is pivotal in tumorigenesis and tumor development [139]. The mechanism of PTEN for tumor suppression involves various pathways, such as FAK [140], the MAPK [141, 142], and the PI3K/AKT pathway [143, 144]. The PI3K/AKT pathway is considered the most critical one for PTEN to exerts its antioncogenic effects. As appears in Fig. 1, PTEN is able to inhibit PI3K/AKT signaling, subsequently triggering cell cycle arrest at the G1 phase and inducing apoptosis in cancer cells [145]. In fact, PTEN level in the CC tissues exhibits a downregulation in contrast to non-carcinoma tissues [117]. Moreover, PTEN expression shows an inverse association with miR-301a, and transfection of miR-301a into HeLa cells inhibits apoptosis through reducing PTEN expression. Also, overexpression of miR-301a upregulates anti-apoptotic factors (BCL2 and MCL1), whereas it suppresses the levels of pro-apoptotic factors (BAD and BAX), thereby inhibiting CC cell apoptosis [117].
Overall, miR-301 inhibits the apoptosis of CC cells through negative regulation of PTEN. In contrast, overexpression of PTEN has been established by Chen et al. [146] which can be targeted by miR-1297 in CC cells. They observed that downregulation of PTEN represses proliferation and suppresses apoptosis in HeLa cell, similar to miR-1297 overexpression. In return, enforced miR-1297 expression suppresses Hela cell apoptosis, maybe by targeting PTEN [146]. More studies are shown in Table 2 and Fig. 1.
Critical role of MiRNAs in regulation cervical cancer cell autophagy
Autophagy is described as a regulated, pivotal catabolic mechanism of responding to extra- or intracellular stress, resulting in cell survival or even autophagic cell death. Therefore, this major processes could occur in malignant cells, and is under extreme regulation of some autophagy‐related genes (ATGs) [147].
Since autophagy is essential for cell survival in harsh situations, and the degradation of intracellular macromolecules (which leads to providing energy for minimal cell functioning in a lack of nutrients), it is challenging to determine the contribution of autophagy to cell survival or death in terms of cancer regulation. Autophagy can be protective in the early stages of cancer progression or act as a tumor suppressor through triggering pro-autophagic genes and suppressing anti‐autophagic ones [147, 148]. However, through regulating various cascades such as Beclin‐1, Bcl‐2, PI3K, mTORC1/C2 and p53, autophagy can serve as a pro‐tumor role in carcinogenesis [149]. In fact, miRNAs are found as critical regulators in the autophagy process [150, 151]. Furthermore, deregulation of autophagy-related miRNAs appears to be correlated with various diseases, such as different types of cancer [152]. Several studies have reported that miRNAs affect CC progression by regulating autophagy. Among them, according to published results, we found that three miRNAs induce autophagy in CC cells (Table 3). In that regard, Wang et al. [153] established that the miR155-5p expression contrasted with the function of autophagic marker proteins (P62 and LC3) in CC tissues. In addition, transfection of miR-155-5p into CC cell lines enhanced autophagy. Furthermore, in contrast to HPV − human cervical tissues, HPV + samples exhibit a downregulated level of miR-155-5p expression and decreased autophagy [153, 154]. Considering the close association of high risk HPV infections with the occurrence of CC [50], HPV infection could result in a suppressed level of miR-155-5p which leads to decreased autophagy [153]. As eluded in Fig. 2 through targeting PDK1, miR-155-5p aggravates CC cells autophagy. In fact, PDK1 serves as a critical junction point for several cell signaling cascades and is always hyperactivated in human cancers. Therefore, PDK1 appears to be a promising target in cancer therapy. PDK1 elevates the activity of mTOR by regulating the PI3K/Akt cascade, thereby suppressing autophagy. PDK1 suppresses cellular autophagy by elevating mTOR activity [155,156,157]. MiR155-5p promotes cell autophagy by suppressing PDK1 and thus suppressing mTOR activity [158]. Wang et al. [153] demonstrated that transfection of mir-155-5p in CC cells elevates autophagy activity while decreasing the expression of PDK1. The effect was reversed after transfection with miR-155-5p inhibitor [153]. Therefore, miR-155-5p increases the CC cell’s autophagy by targeting PDK1. As mentioned above, miR-20a acts as an onco-miRNA and elevates CC progression through apoptosis inhibition and autophagy induction through targeting THBS2. Reduction of miR-20a has shown to reduce proliferation and autophagy while inducing apoptosis by targeting THBS2 in CC cells. In contrast, miR-197 is able to inhibit autophagy by targeting Ring Finger Protein 113 (RNF113A) which can result in suppression of CC progression [159]. In return, miR-204 and − 338 alleviate CC development through suppressing autophagy and elevating apoptosis by targeting Activating transcription factor 2 (ATF-2) [160, 161]. Considering the dual role of autophagy in tumor promotion and suppression, miRNAs can regulate tumorigenesis by both inhibiting and inducing autophagy pathways. So, more studies are needed in this field.
Cancer cell autophagy and regulatory non-coding RNAs. Regulatory microRNAs are highlighted in orange
Several autophagy-related proteins are identified to regulate multiple stages of the autophagy formation. Since their discovery in 1991 [162, 163], more than 40 genes have been identified in yeast that encode Atg proteins [164]. Most of the genes (e.g. Atg1-10, Atg12-14, Atg16-18) are conserved among mammals and yeast, suggesting the evolutionary conservation of the autophagy process [165]. In between, ATG4B is critical for the formation of autophagosomes, thereby appear to be important in cancer treatment through regulating autophagy [166]. Generation of MAP1LC3-I through proteolytic cleavage of cytoplasmic MAP1LC3/LC3 (microtubule- associated protein 1 light chain 3) is a critical step in autophagosome formation, which results in creating membrane-bound MAP1LC3-II [167]. The cysteine protease ATG4B and its paralogs catalyze this essential step, and are also required to recycle MAP1LC3 from the autophagosomal membrane [167, 168]. In that context, targeting ATG4B is established to enhance the chemotherapeutic effect in various cancer cells [169,170,171]. In that regard, pirarubicin (THP) [172], has been introduced as an effective strategy against various tumors while exposing minimum side effects [172,173,174]. However, most CC patients exhibit no sensitivity to THP treatment, which occurs through unknown mechanisms are not clear. Wu et al. [175] confirmed the resistance of CC cells to THP both in vitro and in vivo. In addition, they suggested that THP could induce a macroautophagy/autophagy response in CC cells, and inhibition of this autophagy elevated the cytotoxicity of THP. Moreover, THP elevated the mRNA level of ATG4B in CC cells by enhancing mRNA stability without affecting its transcription. As expected, miRNA regulation is involved in the process, as THP downregulates miR-34c-5p levels which is associated with elevated levels of ATG4B and autophagy (Fig. 2). Upregulation of miR-34c-5p significantly suppresses the level of ATG4B and attenuated autophagy, along with elevated cell death and apoptosis in THP-treated CC cells. Altogether, miR-34-5p promotes CC cell’s sensitivity to pirarubicin through inhibiting pirarubicin-induced autophagy by targeting ATG4B [175]. This provides new insight for elevating the chemotherapeutic effect of THP and further clinical THP therapy for CC.
Moreover, ATG12, among ATG family members that are associated with autophagy could be targeted and subsequently decreased by miR-378 in CC cells. Suggesting miR-378 as an oncogene to promote metastasis and inhibit autophagy through targeting ATG12 in CC [176].
Recently, Tan et al. [176] observed an upregulation in the level of miR-378 and a downregulation in the ATG12 level in CC tissues with lymph node metastasis in contrast to lymph node-negative subjects [176].
As aforementioned, autophagy prevents tumor formation. It has been established that loss of BECLIN 1, the master autophagic gene, results in elevated susceptibility to tumor development [177]. Moreover, autophagy contributes to tumor metabolism and growth during Ras-induced transformation and tumorigenesis [178]. It has been suggested that tumor suppressors modulate autophagy [177]. For instance, AMPK and PTEN induce autophagy, as well, oncogenes that activate mTOR, block autophagy [179]. Recently, Wang et al. [180] established that the relative expression of PTEN mRNA in CC tissue samples is significantly lower than in the normal samples. Also, PTEN mRNA and protein levels in the SiHa and HeLa cells are significantly lower than those in the normal cells [180]. Besides, a negative correlation has been established between the levels of miR-19-3p with PTEN in CC cells. In fact, miR-19-3p is found to be able to target 3′-UTR of PTEN in SiHa and HeLa cells. Furthermore, their data confirmed that ectopic expression of miR-19-3p accelerates CC cell proliferation but suppresses autophagy and apoptosis through targeting PTEN [180]. Similarly, Peralta-Zaragoza et al. demonstrated an inverse association between miR-21 expression and PTEN mRNA level in SiHa cells along with PTEN protein expression in CC cells. Besides, they found that miR-21 negatively regulates the PTEN gene in CC cells by interacting with the MRE21 recognition sites of the PTEN gene. Moreover, miR-21 silencing promotes autophagy and apoptosis of CC cells and reestablishes PTEN gene and protein expression. Overall, miR-21 promotes cervical cancer development by inhibiting autophagy and apoptosis through negatively regulating PTEN. It should be noted that autophagy could contribute to the development of radio-resistance [181]. It might elevate or suppress radio-resistance, depend on the cancer types and tumor microenvironment [181]. Song et al. [182] established that overexpression of miR-21 in radioresistant CC is related to upregulated HIF-1α. In addition, upregulated miR-21 suppresses PTEN, elevates p-Akt, and consequently elevates HIF-1α expression, whereas miR-21 suppression leads to enhanced PTEN, diminished p-Akt, and eventually diminished HIF-1α (Fig. 2). In that regard, through the PTEN/Akt/HIF-1α pathway, miR-21 suppresses autophagy, which is among potential mechanisms of increasing radio-resistance in CC cells [182]. Overall, upregulated miR-21 mediate with HIF-1α aggravates radio-resistance in CC cells by inhibiting autophagy through targeting PTEN. These data expand our knowledge on controlling radio-resistance development in CC by regulating autophagy through microRNAs.
MicroRNAs effect on the ferroptosis, pyroptosis and anoikis in cervical cancer
Ferroptosis
Iron-dependent cell death, termed Ferroptosis, is a unique pathway discovered after exposure of tumor cells to erastin, a small-molecule chemical probe. There are several morphological characteristics for distinguishing ferroptosis from other modes of death, including fractured MOM, reduced mitochondrial volume, a diminished or lack of mitochondrial crest, and a normal-sized nucleus without nuclear concentration [183]. In normal conditions the oxidization of polyunsaturated fatty acids (PUFAs) is due to the function of lipoxygenases such as 12-/15-lipoxygenases. However, a rapid reduction in the levels of lipoxygenase-oxidized PUFAs occurs as a result of the lipid repair enzyme glutathione peroxidase 4 (GPX4) function and its cofactor glutathione (GSH) [184]. Inhibition of the cystine–glutamate antiporter (system Xc−, encompassing subunits SLC3A2 and SLC7A11) induces ferroptosis and results in suppressed GSH biosynthesis and inactivation of GPX4 [185]. Therefore, overwhelming lipid peroxidation leads to subsequent cell death (Fig. 3) [186].
Ferroptosis in cancer cells and regulatory non-coding RNAs. Regulatory microRNAs are highlighted in orange
System XC − inhibitors, including sorafenib and sulfasalazine are compartmentalized as class I ferroptosis-inducing substances [187]. RSL3, which is able to rapidly induce ferroptotic cell death by covalent binding and blocking GPX4, represents class II ferroptosis-inducing substances [185]. The ferroptosis suppressor protein 1 (FSP1) is a flavoprotein that contributes to induction of apoptosis. Initially synthesized in mitochondria, CoQ10 has an essential role in the mitochondrial electron transport chain, and its reduced form, CoQ10H2 is a strong lipophilic antioxidant [188]. FSP1 recruitment to the plasma membrane leads to the exertion of an oxidoreductase function, reducing CoQ10. Subsequently, CoQ10H2 strongly ceased the lipid peroxides dissemination [189]. Since ferroptosis can occur in response to the peroxidation of membrane phospholipids possessing PUFAs [187], enzymes involved in the incorporation of PUFAs into phospholipids are essential for ferroptotic cell death. One example of such a critical enzyme for the execution of ferroptosis is acyl-CoA synthetase long-chain family member 4 (ACSL4) which results in the enrichment of long PUFAs in cell membranes. The autophagy machinery components, including BECN1, ATG3, ATG4B, ATG5, ATG7, and ATG13, can also trigger ferroptosis [37, 190].
Furthermore, the reduction of erastin’s effects on ferroptosis due to diminished levels of intracellular ferrous iron is led by knockout or knockdown of the major genes regulating autophagy [191]. Additionally, ferritinophagy, a proteolytic process that mediates the delivery of ferritin to autophagosomes and engenders reactive oxygen species (ROS), eventually leads to ferroptosis [192, 193]. Noteworthy, miRNA is established to regulate ferroptosis by targeting mRNAs associated with ferroptosis [194,195,196].
Ferroptosis-associated miRNA pose several during tumor metastasis, for instance, in regulation of tumor cells, immune cells, and angiogenesis [195, 197]. For example, miR-506-3p elevates CC cell ferroptosis by targeting CD164 and by promoting the level of MDA, lipid ROS, and iron [198]. Furthermore, miR-515-5p, -409-3P and − 375 promote ferroptosis in HeLa cells by targeting SLC7A11 [199].
Glutathione peroxidase 4 (GPX4) is the core regulator of ferroptosis [200] which is highly regulated at many levels through its expression and synthesis. Targeting GPX4 hold a promise in inducing ferroptosis and eliminating resistant tumors. In that regard, many pharmacological therapeutics are developed to activate ferroptosis through targeting GPX4 in cancer cells [200]. In this regard, Liu et al. [201] suggested that miR-193a-5p can decrease CC cell viability by promoting ferroptosis by targeting GPX4. Besides, they found that circACAP2 enhances CC cell proliferation and viability by positively regulating GPX4 expression levels through sponging miR-193a-5p. The expression of circACAP2 and GPX4 is elevated, and miR-193a-5p expression is decreased in clinical CC samples. The expression of miR-193a-5p exhibits a negative association with circACAP2 and GPX4, whereas the circACAP2 expression has a positive association with GPX4. Also, suppression of miR-193a-5p or upregulation of GPX4 inhibits the circACAP2 depletion-induced lipid ROS, iron, and Fe2 + levels in CC cells [201]. Therefore, miR-193a-5p promotes ferroptosis by targeting GPX4 and serves as tumor suppressor in CC cells (Fig. 3).
Mounting evidence suggested a high occurrence rate for ferroptosis in cancer cells [202]. Sorafenib is an agonist of ferroptosis and is used as the first-line of treatment for advanced hepatocellular carcinoma (HCC). In that regard, in HCC cells, deferoxamine is shown to diminish the toxic effect of sorafenib [203]. ACSLs, a family of enzymes that mediate fatty acid metabolism, are implicated in promoting ferroptosis through producing lipid peroxides, thereby are considered as ferroptosis biomarkers [204]. Xiaofei et al. [205] established that oeanolic acid suppress the proliferation of CC cells by influencing ACSL4-dependent ferroptosis [205]. Additionally, upregulated circular RNA circEPSTI1 elevates CC growth through negative regulation of SLC7A11-dependent ferroptosis [206]. MiR-4291 as onco-miRNA contributes to CC development by inhibiting ferroptosis. Mechanically, miR-4291 suppresses ferroptosis in C33A and CaSki cells through negative regulation of ACSL4 expression. In return, circLMO1 downregulates CC growth and metastasis by promoting ferroptosis through sponging miR-4291 and positively regulating ACSL4 levels [207].
Pyroptosis
Pyroptosis, a more recently discovered PCD, is under the regulation of inflammatory caspases that coordinate biological effects [208, 209]. Various factors trigger pyroptosis cell removal. For instance, activated inflammatory caspase trigger the removal of cells [210], plasma membrane pores developed by the activated inflammatory caspase, result in swelling of cells resultant of water uptake and consequent cell lysis which occurs through disrupting the plasma membrane. Also, the disruption of membrane and leakage of cytosolic components (e.g., interleukin (IL)-1β and − 18) to the extracellular environment, amplifies the local or systemic inflammatory influences [211, 212]. Various molecular mechanisms and signaling cascades are implicated in the regulation of pyroptosis, yet, little is known about the miRNA’s participations to this process. However, as far as we know, the role of only miR-214 and miR-124 in the regulation of pyroptosis in CC cells has been investigated (Table 4). Yu et al. [213] reported that in CC individuals, miR-214 and NLRP3 are downregulated. Also, the level of pyroptosis-related genes expression, such as NLRP1/3, NLRC4, caspase-1, IL-18, and − 1β are suppressed in the CC tissues. Their results established that enforcing the expression of miR-214 in Hela cells leads to inducing pyroptosis and suppresses the proliferation of CC cells by enhancing the expression of NLRP3 [213]. Similarly, miR-124 alleviates the CC pyroptosis by targeting SIRT1 (Fig. 4) [214]. According to the regulatory role of miRNAs in CC cells may mediate pyroptosis and may provide potential targets against the progression of cervical cancer. However, very limited studies have been focused on the role of miRNAs in the regulation of pyroptosis in CC, and require more attention from researchers in the future.
Pyroptosis pathway in cancer cells and regulatory microRNAs. Regulatory microRNAs are highlighted in orange
Anoikis
The interruption of cell–cell attachment or cell-ECM attachment results in the formation of apoptotic cell death, known as “anoikis” [215]. Anoikis has been described as a mechanism for eliminating misplaced or detached cells under physiological or pathological circumstances, which eases tissue homeostasis [216, 217]. In tumor cells, anoikis retards cell metastasis, and in addition, anoikis could occur in diabetes and cardiovascular disorders [216]. Similar to apoptosis, the initiation of anoikis occurs by the activation of the intrinsic and extrinsic pathways [42, 215]. Anoikis resistance takes place if the detached cells circumvent death signaling cascades, which enables the survival of cells as a consequence of various changes within the cell. Bcl-2 is considered a marker of the anoikis intrinsic cascade [218]. Furthermore, anoikis resistance could facilitate metastasis through promoting EMT [215]. Anoikis resistant cells exhibits malignant behaviors, such as rapid proliferation, enhanced anti-apoptotic protein levels, and an EMT phenotype. Growing evidence has established that several miRNAs expose aberrant expression levels and control metastasis-related processes, including invasion, EMT or anoikis [218,219,220]. High expression of miR-525-5p, an identified tumor suppressor in many malignant tumors, prevents anoikis resistance and growth independent of anchorage in CC cells. Higher expression of miR-525-5p has been demonstrated to elevate Bax expression, the predominant pro-apoptotic protein in anoikis, and suppress Bcl-2 expression, which is the major anti-apoptotic protein in anoikis [221]. Ubiquitin-conjugating enzyme E2C (UBE2C), a potential oncogene, is implicated in tumorigenesis or tumor progression [222]. Upregulation of UBE2C has been established in CC individuals and cell lines [223, 224]. In addition, UBE2C contributes to cancer progression, invasion, and metastasis through inducing EMT and regulating of angiogenic responses [223]. ZEB1/2 (zinc fnger E-box binding homeobox 1/2) are transcription factors that are aberrantly expressed in CC [225]. In fact, ZEB1/2 are identified to elevate invasion and EMT in CC cells and are upregulated after they are directly targeted by UBE2C [226,227,228,229]. Recently, Chen et al. [230] demonstrated that UBE2C itself is directly targeted by miR-525-5p, suggesting that miR-525-5p can downregulate the levels of ZEB1/2 expression. Therefore, miR-525-5p/UBE2C/ ZEB1/2 pathway is found to mediate CC progression. Besides, they found that miR-525-5p suppressed adhesion to trigger the EMT but elevated anoikis to inhibit metastasis through interrupting UBE2C/ZEB1/2 signaling cascade [230]. Therefore, this data established the roles of miR-525-5p in CC metastases, which contributed to anoikis resistance and anchorage-independent growth, thereby suggesting miR-525-5p as a target for CC treatment.
Conclusion and future perspective
The promotion of cell death through microRNAs (miRNAs) presents a promising avenue for the development of anticancer therapies, particularly for solid tumors such as cervical cancer. Two primary strategies can be employed to harness the potential of miRNAs in this context: the first involves the therapeutic replacement of miRNAs that induce apoptosis in cancer cells, while the second focuses on the selective silencing of anti-programmed cell death (anti-PCD) miRNAs. The reduction of anti-PCD miRNAs is crucial, as these molecules inhibit programmed cell death, thereby facilitating cancer cell survival and contributing to resistance against chemotherapeutic agents [231, 232].
To effectively suppress miRNA activity, the use of miRNA inhibitors and oligomers is a viable approach. Additionally, modified miRNA mimetics, such as plasmid or lentiviral vectors that express specific miRNA sequences, may enhance the function of miRNAs that promote cancer cell death. While restoring normal miRNA expression holds significant therapeutic promise, challenges remain due to the incomplete understanding of miRNA regulation and function during their biogenesis and in the context of tumorigenesis.
To mitigate potential adverse effects associated with miRNA therapies, it is essential to investigate the immunogenic and cytotoxic impacts of in vivo miRNA delivery. Furthermore, the role of miRNAs within the complex transcription factor-like gene regulatory networks complicates the feasibility of knocking down miRNAs using anti-miRNA oligonucleotides. Current limitations in the delivery and distribution systems for miRNAs pose additional challenges to their therapeutic application. Biological vectors, such as adeno-associated viruses and lentiviruses, can facilitate targeted delivery; however, it is imperative to avoid unintended off-target effects [233].
The dual role of many miRNAs as either tumor suppressors or oncogenes, depending on the cellular context, etiology, and cancer stage, underscores the complexity of miRNA networks in tumorigenesis [234]. The intricate interplay of miRNA species derived from the 5p and 3p arms of pre-miRNA precursors further complicates their functional roles. Emerging evidence suggests that some miRNAs can regulate multiple forms of programmed cell death, making them attractive targets for overcoming resistance to cell death and enhancing sensitivity to chemotherapy in cervical cancer cells [133, 134].
The ability of miRNAs to modulate oncogenes and tumor suppressor genes positions them as potential biomarkers for early diagnosis and prognosis, as well as therapeutic targets. As we look towards the future, the implications of miRNA research could be profound, particularly in the context of personalized medicine. Advances in miRNA profiling may enable the development of tailored therapies that enhance treatment efficacy while minimizing side effects. The anticipated 2024 Nobel Prize in Medicine may further spotlight the significance of miRNAs, potentially recognizing groundbreaking discoveries that elucidate their mechanisms in cancer biology. Such recognition could catalyze increased funding and interest in miRNA-based therapies, ultimately leading to innovative treatment strategies for solid tumors like cervical cancer. However, the mechanisms underlying miRNA action remain incompletely understood, necessitating further basic research and clinical trials to validate their therapeutic applicability. As translational research progresses, a deeper understanding of miRNA dynamics and their interactions within cellular networks will be essential for developing effective therapies for solid tumors like cervical cancer [235, 236].
Data availability
No datasets were generated or analysed during the current study.
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68(6):394–424.
Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019;393(10167):169–82.
Ries L, Melbert D, Krapcho M, Mariotto A, Miller B, Feuer E et al. SEER cancer statistics review, 1975–2004. National Cancer Institute; Bethesda, MD: 2007. 2007.
Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, et al. Cervical cancer: a global health crisis. Cancer. 2017;123(13):2404–12.
Poddar P, Maheshwari A. Surgery for cervical cancer: consensus & controversies. Indian J Med Res. 2021;154(2):284–92.
Fontham ETH, Wolf AMD, Church TR, Etzioni R, Flowers CR, Herzig A, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American cancer society. Cancer J Clin. 2020;70(5):321–46.
Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382(9895):889–99.
Wang H, Zhou X, Li C, Yan S, Feng C, He J, et al. The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy. J Hematol Oncol. 2022;15(1):1–21.
Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. 2022;15(1):174.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25(3):486–541.
Peng F, Liao M, Qin R, Zhu S, Peng C, Fu L, et al. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Target Therapy. 2022;7(1):286.
Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29(5):347–64.
Koren E, Fuchs Y. Modes of regulated cell death in cancer. Cancer Discov. 2021;11(2):245–65.
Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, et al. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 2012;45(6):487–98.
Towers CG, Wodetzki D, Thorburn A. Autophagy and cancer: modulation of cell death pathways and cancer cell adaptations. J Cell Biol. 2019;219(1):e201909033.
Wang H, Liu M, Zeng X, Zheng Y, Wang Y, Zhou Y. Cell death affecting the progression of gastric cancer. Cell Death Discovery. 2022;8(1):377.
Chen X, Zeh HJ, Kang R, Kroemer G, Tang D. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Reviews Gastroenterol Hepatol. 2021;18(11):804–23.
Wang X, Wu S, Liu F, Ke D, Wang X, Pan D, et al. An immunogenic cell death-related classification predicts prognosis and response to immunotherapy in head and neck squamous cell carcinoma. Front Immunol. 2021;12:781466.
Mirzaei H, Rahimian N, Mirzaei HR, Nahand JS, Hamblin MR. Exosomes and MicroRNAs in biomedical science. Morgan & Claypool; 2022.
Mirzaei H, Rahimian N, Mirzaei HR, Nahand JS, Hamblin MR. MicroRNA biogenesis and function. Exosomes and MicroRNAs in biomedical science. Springer; 2022. pp. 1–9.
Rahimian N, Nahand JS, Hamblin MR, Mirzaei H. Exosomal MicroRNA profiling. MicroRNA Profiling: Methods and Protocols. 2022:13–47.
Hussen BM, Ahmadi G, Marzban H, Azar MEF, Sorayyayi S, Karampour R, et al. The role of HPV gene expression and selected cellular MiRNAs in lung cancer development. Microb Pathog. 2021;150:104692.
Abbasi-Kolli M, Nahand JS, Kiani SJ, Khanaliha K, Khatami AR, Taghizadieh M et al. The expression patterns of MALAT-1, NEAT-1, THRIL, and miR-155-5p in the acute to the post-acute phase of COVID-19 disease. Brazilian J Infect Dis. 2022;26.
Garofalo M, Condorelli G, Croce C, Condorelli G. MicroRNAs as regulators of death receptors signaling. Cell Death Differ. 2010;17(2):200–8.
Palumbo S, Miracco C, Pirtoli L, Comincini S. Emerging roles of MicroRNA in modulating cell-death processes in malignant glioma. J Cell Physiol. 2014;229(3):277–86.
O’Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol. 2018;9:402.
Khvorova A, Reynolds A, Jayasena SD. Functional SiRNAs and MiRNAs exhibit strand bias. Cell. 2003;115(2):209–16.
Almeida MI, Nicoloso MS, Zeng L, Ivan C, Spizzo R, Gafà R, et al. Strand-specific miR-28-5p and miR-28-3p have distinct effects in colorectal cancer cells. Gastroenterology. 2012;142(4):886–96. e9.
Jiang L, Huang Q, Zhang S, Zhang Q, Chang J, Qiu X, et al. Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells. BMC Cancer. 2010;10(1):1–13.
Yilmaz SG, Isbir S, Kunt AT, Isbir T. Circulating MicroRNAs as novel biomarkers for atherosclerosis. Vivo. 2018;32(3):561–5.
Yousefpouran S, Mostafaei S, Manesh PV, Iranifar E, Bokharaei-Salim F, Nahand JS, et al. The assessment of selected MiRNAs profile in HIV, HBV, HCV, HIV/HCV, HIV/HBV co-infection and elite controllers for determination of biomarker. Microb Pathog. 2020;147:104355.
Letafati A, Najafi S, Mottahedi M, Karimzadeh M, Shahini A, Garousi S, et al. MicroRNA let-7 and viral infections: focus on mechanisms of action. Cell Mol Biol Lett. 2022;27(1):14.
Hussen BM, Ahmadi G, Marzban H, Fard Azar ME, Sorayyayi S, Karampour R, et al. The role of HPV gene expression and selected cellular MiRNAs in lung cancer development. Microb Pathog. 2021;150:104692.
Abbasi-Kolli M, Sadri Nahand J, Kiani SJ, Khanaliha K, Khatami A, Taghizadieh M, et al. The expression patterns of MALAT-1, NEAT-1, THRIL, and miR-155-5p in the acute to the post-acute phase of COVID-19 disease. Braz J Infect Dis. 2022;26(3):102354.
Sadri Nahand J, Salmaninejad A, Mollazadeh S, Tamehri Zadeh SS, Rezaee M, Sheida AH, et al. Virus, exosome, and MicroRNA: new insights into autophagy. Adv Exp Med Biol. 2022;1401:97–162.
Fairlie WD, Tran S, Lee EF. Crosstalk between apoptosis and autophagy signaling pathways. Int Rev Cell Mol Biology. 2020;352:115–58.
Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91–8.
Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev Immunol. 2018;36:489–517.
Nahand JS, Shojaie L, Akhlagh SA, Ebrahimi MS, Mirzaei HR, Baghi HB, et al. Cell death pathways and viruses: role of MicroRNAs. Mol Therapy-Nucleic Acids. 2021;24:487–511.
Shamas-Din A, Kale J, Leber B, Andrews DW. Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol. 2013;5(4):a008714.
Zhang J, Huang K, O’Neill K, Pang X, Luo X. Bax/Bak activation in the absence of bid, Bim, Puma, and p53. Cell Death Dis. 2016;7(6):e2266–e.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.
Parrish AB, Freel CD, Kornbluth S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol. 2013;5(6):a008672.
Patel V, Balakrishnan K, Keating MJ, Wierda WG, Gandhi V. Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells. Blood J Am Soc Hematol. 2015;125(7):1126–36.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are MicroRNA targets. Cell. 2005;120(1):15–20.
Pu M, Chen J, Tao Z, Miao L, Qi X, Wang Y, et al. Regulatory network of MiRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression. Cell Mol Life Sci. 2019;76:441–51.
Miao J, Regenstein JM, Xu D, Zhou D, Li H, Zhang H, et al. The roles of MicroRNA in human cervical cancer. Arch Biochem Biophys. 2020;690:108480.
Nahand JS, Taghizadeh-boroujeni S, Karimzadeh M, Borran S, Pourhanifeh MH, Moghoofei M, et al. MicroRNAs: new prognostic, diagnostic, and therapeutic biomarkers in cervical cancer. J Cell Physiol. 2019;234(10):17064–99.
Nahand JS, Vandchali NR, Darabi H, Doroudian M, Banafshe HR, Moghoofei M, et al. Exosomal MicroRNAs: novel players in cervical cancer. Epigenomics. 2020;12(18):1651–60.
Sadri Nahand J, Moghoofei M, Salmaninejad A, Bahmanpour Z, Karimzadeh M, Nasiri M, et al. Pathogenic role of exosomes and MicroRNAs in HPV-mediated inflammation and cervical cancer: a review. Int J Cancer. 2020;146(2):305–20.
Alajez NM, Lenarduzzi M, Ito E, Hui AB, Shi W, Bruce J, et al. MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer Res. 2011;71(6):2381–91.
Jia Z, Jiang L, Wang H, Gao W. MiR-218 restrains proliferation of cervical cancer cells via targeted regulation of HMGB1/RAGE pathway. J BUON: Official J Balkan Union Oncol. 2020;25(6):2683–9.
Liu Z, Mao L, Wang L, Zhang H, Hu X. miR–218 functions as a tumor suppressor gene in cervical cancer. Mol Med Rep. 2020;21(1):209–19.
Yu M, Xu B, Yang H, Xue S, Zhang R, Zhang H, et al. MicroRNA-218 regulates the chemo-sensitivity of cervical cancer cells through targeting survivin. Cancer Manage Res. 2019;11:6511–9.
Yuan W, Xiaoyun H, Haifeng Q, Jing L, Weixu H, Ruofan D, et al. MicroRNA-218 enhances the radiosensitivity of human cervical cancer via promoting radiation induced apoptosis. Int J Med Sci. 2014;11(7):691–6.
Li J, Ping Z, Ning H. MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer. Int J Mol Sci. 2012;13(12):16053–64.
Zhu L, Tu H, Liang Y, Tang D. MiR-218 produces anti-tumor effects on cervical cancer cells in vitro. World J Surg Oncol. 2018;16(1):204.
Kurita S, Mott J, Almada L, Bronk S, Werneburg N, Sun S, et al. GLI3-dependent repression of DR4 mediates Hedgehog antagonism of TRAIL-induced apoptosis. Oncogene. 2010;29(34):4848–58.
Wen S, Lin Y, Yu Y, Cao S, Zhang R, Yang X, et al. miR-506 acts as a tumor suppressor by directly targeting the Hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene. 2015;34(6):717–25.
Li J, Qiu M, An Y, Huang J, Gong C. miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the Hedgehog pathway factor Gli3. Biochem Biophys Res Commun. 2018;503(3):2101–7.
Zhang J, Li S, Li Y, Liu H, Zhang Y, Zhang Q. miRNA-218 regulates the proliferation and apoptosis of cervical cancer cells via targeting Gli3. Exp Ther Med. 2018;16(3):2433–41.
He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Therapy. 2021;6(1):425.
Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci. 2003;116(8):1409–16.
Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005;6(1):56–68.
Sonoda Y, Watanabe S, Matsumoto Y, Aizu-Yokota E, Kasahara T. FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. J Biol Chem. 1999;274(15):10566–70.
Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T. Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem. 2000;275(21):16309–15.
Kasahara T, Koguchi E, Funakoshi M, Aizu-Yokota E, Sonoda Y. Antiapoptotic action of focal adhesion kinase (FAK) against ionizing radiation. Antioxid Redox Signal. 2002;4(3):491–9.
Yamamoto D, Sonoda Y, Hasegawa M, Funakoshi-Tago M, Aizu-Yokota E, Kasahara T. FAK overexpression upregulates Cyclin D3 and enhances cell proliferation via the PKC and PI3-kinase-Akt pathways. Cell Signal. 2003;15(6):575–83.
Reif S, Lang A, Lindquist JN, Yata Y, Gabele E, Scanga A, et al. The role of focal adhesion kinase-phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type I collagen expression. J Biol Chem. 2003;278(10):8083–90.
Hu G, Wei Y, Kang Y. The multifaceted role of MTDH/AEG-1 in cancer progression. Clin Cancer Res. 2009;15(18):5615–20.
Zhang J, Zhang Y, Liu S, Zhang Q, Wang Y, Tong L, et al. Metadherin confers chemoresistance of cervical cancer cells by inducing autophagy and activating ERK/NF-κB pathway. Tumor Biology. 2013;34:2433–40.
Hu K, Mu X, Kolibaba H, Yin Q, Liu C, Liang X, et al. Metadherin is an apoptotic modulator in prostate cancer through miR-342-3p regulation. Saudi J Biol Sci. 2018;25(5):975–81.
Yang L, Tian Y, Leong WS, Song H, Yang W, Wang M, et al. Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro. Breast Cancer Res. 2018;20(1):113.
Huang K, Li LA, Meng Y, You Y, Fu X, Song L. High expression of astrocyte elevated gene-1 (AEG-1) is associated with progression of cervical intraepithelial neoplasia and unfavorable prognosis in cervical cancer. World J Surg Oncol. 2013;11:297.
Long M, Dong K, Gao P, Wang X, Liu L, Yang S, et al. Overexpression of astrocyte-elevated gene-1 is associated with cervical carcinoma progression and angiogenesis. Oncol Rep. 2013;30(3):1414–22.
Liang C, Ding J, Yang Y, Deng L, Li X. MicroRNA-433 inhibits cervical cancer progression by directly targeting metadherin to regulate the AKT and β-catenin signalling pathways. Oncol Rep. 2017;38(6):3639–49.
Park HA, Broman K, Jonas EA. Oxidative stress battles neuronal Bcl-xL in a fight to the death. Neural Regen Res. 2021;16(1):12–5.
Arbab IA, Looi CY, Abdul AB, Cheah FK, Wong WF, Sukari MA et al. Dentatin induces apoptosis in prostate cancer cells via Bcl-2, Bcl-xL, survivin downregulation, caspase-9, -3/7 activation, and NF-κB inhibition. Evidence-based complementary and alternative medicine: eCAM. 2012;2012:856029.
Siddiqui WA, Ahad A, Ahsan H. The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol. 2015;89(3):289–317.
Chen X-F, Liu Y. MicroRNA-744 inhibited cervical cancer growth and progression through apoptosis induction by regulating Bcl-2. Biomed Pharmacother. 2016;81:379–87.
Liu S, Wang H, Mu J, Wang H, Peng Y, Li Q, et al. MiRNA-211 triggers an autophagy-dependent apoptosis in cervical cancer cells: regulation of Bcl-2. Naunyn Schmiedebergs Arch Pharmacol. 2020;393:359–70.
He C, Yang J. miR-187 induces apoptosis of SiHa cervical carcinoma cells by downregulating Bcl-2. Genet Mol Res. 2017;16(1).
Hu QL, Xu ZP, Lan YF, Li B. miR-636 represses cell survival by targeting CDK6/Bcl‐2 in cervical cancer. Kaohsiung J Med Sci. 2020;36(5):328–35.
Gibson L, Holmgreen SP, Huang D, Bernard O, Copeland NG, Jenkins NA, et al. bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene. 1996;13(4):665–75.
Yasui K, Mihara S, Zhao C, Okamoto H, Saito-Ohara F, Tomida A, et al. Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res. 2004;64(4):1403–10.
Santos-Beneit AM, Mollinedo F. Expression of genes involved in initiation, regulation, and execution of apoptosis in human neutrophils and during neutrophil differentiation of HL-60 cells. J Leukoc Biol. 2000;67(5):712–24.
Nahand JS, Rabiei N, Fathazam R, Taghizadieh M, Ebrahimi MS, Mahjoubin-Tehran M, et al. Oncogenic viruses and chemoresistance: what do we know? Pharmacol Res. 2021;170:105730.
Kawasaki T, Yokoi S, Tsuda H, Izumi H, Kozaki Ki, Aida S, et al. BCL2L2 is a probable target for novel 14q11. 2 amplification detected in a non-small cell lung cancer cell line. Cancer Sci. 2007;98(7):1070–7.
Lee HW, Lee S-S, Lee SJ, Um H-D. Bcl-w is expressed in a majority of infiltrative gastric adenocarcinomas and suppresses the cancer cell death by blocking stress-activated protein kinase/c-Jun NH2-terminal kinase activation. Cancer Res. 2003;63(5):1093–100.
Wilson JW, Nostro M, Balzi M, Faraoni P, Cianchi F, Becciolini A, et al. Bcl-w expression in colorectal adenocarcinoma. Br J Cancer. 2000;82(1):178–85.
Wang F, Liu M, Li X, Tang H. MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells. FEBS Lett. 2013;587(5):488–95.
Bayat M, Sadri Nahand J. Exosomal MiRNAs: the Tumor’s Trojan horse in selective metastasis. Mol Cancer. 2024;23(1):167.
Bayat M, Nahand JS. Let’s make it personal: CRISPR tools in manipulating cell death pathways for cancer treatment. Cell Biol Toxicol. 2024;40(1):61.
Galluzzi L, Spetz JK. Cell death regulation in health and disease-part. Academic; 2020.
Zhang T, Zou P, Wang T, Xiang J, Cheng J, Chen D, et al. Down-regulation of miR-320 associated with cancer progression and cell apoptosis via targeting Mcl-1 in cervical cancer. Tumor Biology. 2016;37(7):8931–40.
McDermott N, Meunier A, Lynch TH, Hollywood D, Marignol L. Isogenic radiation resistant cell lines: development and validation strategies. Int J Radiat Biol. 2014;90(2):115–26.
Mladenov E, Magin S, Soni A, Iliakis G. DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy. Front Oncol. 2013;3:113.
Darvish L, Bahreyni Toossi MT, Azimian H, Shakeri M, Dolat E, Ahmadizad Firouzjaei A, et al. The role of microRNA-induced apoptosis in diverse radioresistant cancers. Cell Signal. 2023;104:110580.
Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, et al. Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology. 2010;51(3):836–45.
Wang Y, Zhang X, Li H, Yu J, Ren X. The role of miRNA-29 family in cancer. Eur J Cell Biol. 2013;92(3):123–8.
Kesheh MM, Bayat M, Kobravi S, Lotfalizadeh MH, Heydari A, Memar MY, et al. MicroRNAs and human viral diseases: a focus on the role of microRNA-29. Biochimica et biophysica acta (BBA) -. Mol Basis Disease. 2025;1871(1):167500.
Chuang PC, Chen PT, Wang CC, Su WH, Chen YH, Huang EY. MicroRNA-29a manifests multifaceted features to intensify radiosensitivity, escalate apoptosis, and revoke cell migration for palliating radioresistance-enhanced cervical cancer progression. Int J Mol Sci. 2022;23(10).
Zhou M, Chen X, Wu J, He X, Ren R. MicroRNA–143 regulates cell migration and invasion by targeting GOLM1 in cervical cancer. Oncol Lett. 2018;16(5):6393–400.
Li J, Liu Q, Clark LH, Qiu H, Bae-Jump VL, Zhou C. Deregulated MiRNAs in human cervical cancer: functional importance and potential clinical use. Future Oncol. 2017;13(8):743–53.
Liu L, Yu X, Guo X, Tian Z, Su M, Long Y, et al. miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol Med Rep. 2012;5(3):753–60.
Zhang L, Zhang X-J, Lu Y. MiRNA-143 mediates the proliferative signaling pathway of FSH and regulates estradiol production. 2017.
Gong Y, Wan JH, Zou W, Lian GY, Qin JL, Wang QM. MiR-29a inhibits invasion and metastasis of cervical cancer via modulating methylation of tumor suppressor SOCS1. Future oncology (London, England). 2019;15(15):1729–44.
Wang H, Li Q, Niu X, Wang G, Zheng S, Fu G, et al. miR-143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling. Oncol Lett. 2017;13(1):435–40.
Qian X, Yu J, Yin Y, He J, Wang L, Li Q, et al. MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers. Cell Cycle (Georgetown Tex). 2013;12(9):1385–94.
Esfandyari YB, Doustvandi MA, Amini M, Baradaran B, Zaer SJ, Mozammel N, et al. MicroRNA-143 sensitizes cervical cancer cells to cisplatin: a promising anticancer combination therapy. Reproductive Sci. 2021;28:2036–49.
Fu Z, Chen D, Cheng H, Wang F. Hypoxia-inducible factor-1α protects cervical carcinoma cells from apoptosis induced by radiation via modulation of vascular endothelial growth factor and p53 under hypoxia. Med Sci Monitor: Int Med J Experimental Clin Res. 2015;21:318–25.
Zhao Y, Liu X, Lu Y-X. MicroRNA-143 regulates the proliferation and apoptosis of cervical cancer cells by targeting HIF-1α. Eur Rev Med Pharmacol Sci. 2017;21(24).
Liu M, Jia J, Wang X, Liu Y, Wang C, Fan R. Long non-coding RNA HOTAIR promotes cervical cancer progression through regulating BCL2 via targeting miR-143-3p. Cancer Biol Ther. 2018;19(5):391–9.
Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther. 2004;1(4):279–93.
Wang HW, Zhang LL, Miao F, Lv T, Wang XL, Huang Z. Treatment of HPV infection-associated cervical condylomata acuminata with 5-aminolevulinic acid-mediated photodynamic therapy. Photochem Photobiol. 2012;88(3):565–9.
Li T, Li M, Xu C, Xu X, Ding J, Cheng L, et al. miR–146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF–κB signaling by targeting TRAF6. Oncol Rep. 2019;41(5):2897–908.
Cai Y, Zhang K, Cao L, Sun H, Wang H. Inhibition of Microrna-766-5p attenuates the development of cervical cancer through regulating SCAI. Technol Cancer Res Treat. 2020;19:1533033820980081.
Qiu Z, He L, Yu F, Lv H, Zhou Y. LncRNA FAM13A-AS1 regulates proliferation and apoptosis of cervical cancer cells by targeting miRNA-205-3p/DDI2 axis. J Oncol. 2022;2022:8411919.
Sanches JGP, Xu Y, Yabasin IB, Li M, Lu Y, Xiu X, et al. miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD. Chemico-Biol Interact. 2018;285:85–95.
Li S, Yang F, Wang M, Cao W, Yang Z. miR-378 functions as an onco-miRNA by targeting the ST7L/Wnt/β-catenin pathway in cervical cancer. Int J Mol Med. 2017;40(4):1047–56.
Dang H, Zheng P, Liu Y, Wu X, Wu X. MicroRNA-543 acts as a prognostic marker and promotes the cell proliferation in cervical cancer by BRCA1-interacting protein 1. Tumor Biology. 2017;39(2):1010428317691187.
Tong R, Zhang J, Wang C, Li Q, Wang L, Ju M. Inhibition of miR-574-5p suppresses cell growth and metastasis and enhances chemosensitivity by targeting RNA binding protein QKI in cervical cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(6):951–66.
Ni Z, Shen Y, Wang W, Cheng X, Fu Y. miR-141-5p affects the cell proliferation and apoptosis by targeting BTG1 in cervical cancer. Cancer Biotherapy & Radiopharmaceuticals; 2021.
Zhao X-Q, Tang H, Yang J, Gu X-Y, Wang S-M, Ding Y. MicroRNA-15a-5p down-regulation inhibits cervical cancer by targeting TP53INP1 in vitro. Eur Rev Med Pharmacol Sci. 2019;23:19.
Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, et al. Thrombospondin-1 and-2 messenger RNA expression in invasive cervical cancer: correlation with angiogenesis and prognosis. Clin Cancer Res. 2001;7(9):2826–31.
Sun R, Wu J, Chen Y, Lu M, Zhang S, Lu D, et al. Down regulation of Thrombospondin2 predicts poor prognosis in patients with gastric cancer. Mol Cancer. 2014;13(1):1–10.
Zhuo C, Li X, Zhuang H, Tian S, Cui H, Jiang R, et al. Elevated THBS2, COL1A2, and SPP1 expression levels as predictors of gastric cancer prognosis. Cell Physiol Biochem. 2016;40(6):1316–24.
Chijiwa T, Abe Y, Inoue Y, Matsumoto H, Kawai K, Matsuyama M, et al. Cancerous, but not stromal, thrombospondin-2 contributes prognosis in pulmonary adenocarcinoma. Oncol Rep. 2009;22(2):279–83.
Matos A, Coutinho-Camillo C, Thuler L, Fonseca F, Soares F, Silva E, et al. Expression analysis of thrombospondin 2 in prostate cancer and benign prostatic hyperplasia. Exp Mol Pathol. 2013;94(3):438–44.
Zhou Q, Dong J, Luo R, Zhou X, Wang J, Chen F. MicroRNA-20a regulates cell proliferation, apoptosis and autophagy by targeting thrombospondin 2 in cervical cancer. Eur J Pharmacol. 2019;844:102–9.
Du P, Lai YH, Yao DS, Chen JY, Ding N. Downregulation of microRNA-1246 inhibits tumor growth and promotes apoptosis of cervical cancer cells by targeting thrombospondin-2. Oncol Lett. 2019;18(3):2491–9.
Xu H, Zhu J, Hu C, Song H, Li Y. Inhibition of microRNA-181a may suppress proliferation and invasion and promote apoptosis of cervical cancer cells through the PTEN/Akt/FOXO1 pathway. J Physiol Biochem. 2016;72(4):721–32.
Yang L, Wang Y-L, Liu S, Zhang P-P, Chen Z, Liu M, et al. miR-181b promotes cell proliferation and reduces apoptosis by repressing the expression of adenylyl cyclase 9 (AC9) in cervical cancer cells. FEBS Lett. 2014;588(1):124–30.
Ke G, Liang L, Yang JM, Huang X, Han D, Huang S, et al. MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene. Oncogene. 2013;32(25):3019–27.
Santiago-Walker AE, Fikaris AJ, Kao GD, Brown EJ, Kazanietz MG, Meinkoth JL. Protein kinase C delta stimulates apoptosis by initiating G1 phase cell cycle progression and S phase arrest. J Biol Chem. 2005;280(37):32107–14.
Brodie C, Blumberg PM. Regulation of cell apoptosis by protein kinase C delta. Apoptosis. 2003;8(1):19–27.
Ke G, Liang L, Yang J, Huang X, Han D, Huang S, et al. MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene. Oncogene. 2013;32(25):3019–27.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Volume 275. New York, NY: Science; 1997. pp. 1943–7. 5308.
Mutter GL. Pten, a protean tumor suppressor. Am J Pathol. 2001;158(6):1895–8.
Cheng Z, Guo X, Li S, Wang S, Yang X, Xue F, et al. The role of PTEN-FAK signaling pathway in metastasis and invasive ability of leukemia cells. Zhonghua Xue ye Xue Za Zhi = Zhonghua. Xueyexue Zazhi. 2009;30(2):115–20.
She QB, Solit DB, Ye Q, O’Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005;8(4):287–97.
Bouali S, Chrétien AS, Ramacci C, Rouyer M, Becuwe P, Merlin JL. PTEN expression controls cellular response to cetuximab by mediating PI3K/AKT and RAS/RAF/MAPK downstream signaling in KRAS wild-type, hormone refractory prostate cancer cells. Oncol Rep. 2009;21(3):731–5.
Ding J, Ning B, Gong W, Wen W, Wu K, Liang J, et al. Cyclin D1 induction by benzo[a]pyrene-7,8-diol-9,10-epoxide via the phosphatidylinositol 3-kinase/Akt/MAPK- and p70s6k-dependent pathway promotes cell transformation and tumorigenesis. J Biol Chem. 2009;284(48):33311–9.
Gao Q, Ye F, Xia X, Xing H, Lu Y, Zhou J, et al. Correlation between PTEN expression and PI3K/Akt signal pathway in endometrial carcinoma. Journal of Huazhong university of science and technology medical sciences = Hua Zhong Ke Ji Da Xue Xue Bao Yi Xue Ying de Wen ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban. 2009;29(1):59–63.
Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Sci (New York NY). 1998;280(5369):1614–7.
Chen Z, Zhang M, Qiao Y, Yang J, Yin Q. MicroRNA-1297 contributes to the progression of human cervical carcinoma through PTEN. Artif Cells Nanomed Biotechnol. 2018;46(sup2):1120–6.
Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7(12):961–7.
Choi KS. Autophagy and cancer. Exp Mol Med. 2012;44(2):109–20.
Kundu M, Thompson CB. Autophagy: basic principles and relevance to disease. Annu Rev Pathol Mech Dis. 2008;3:427–55.
Shan C, Chen X, Cai H, Hao X, Li J, Zhang Y, et al. The emerging roles of autophagy-related MicroRNAs in cancer. Int J Biol Sci. 2021;17(1):134–50.
Sadri Nahand J, Salmaninejad A, Mollazadeh S, Tamehri Zadeh SS, Rezaee M, Sheida AH, et al. Virus, exosome, and MicroRNA: new insights into autophagy. In: Turksen K, editor. Cell biology and translational medicine, volume 17: stem cells in tissue differentiation, regulation and disease. Cham: Springer Nature Switzerland; 2022. pp. 97–162.
Gozuacik D, Akkoc Y, Ozturk DG, Kocak M. Autophagy-regulating MicroRNAs and cancer. Front Oncol. 2017;7:65.
Wang F, Shan S, Huo Y, Xie Z, Fang Y, Qi Z, et al. MiR-155-5p inhibits PDK1 and promotes autophagy via the mTOR pathway in cervical cancer. Int J Biochem Cell Biol. 2018;99:91–9.
Bayat M, Golestani S, Motlaghzadeh S, Bannazadeh Baghi H, Lalehzadeh A, Sadri Nahand J. War or peace: viruses and metastasis. Biochim Et Biophys Acta (BBA) - Reviews Cancer. 2024;1879(6):189179.
He J, Yu S, Guo C, Tan L, Song X, Wang M, et al. Polyphyllin I induces autophagy and cell cycle arrest via inhibiting PDK1/Akt/mTOR signal and downregulating Cyclin B1 in human gastric carcinoma HGC-27 cells. Biomed Pharmacother. 2019;117:109189.
Kim EJ, Kim GT, Kim BM, Lim EG, Kim S-Y, Kim YM. Apoptosis-induced effects of extract from Artemisia annua Linné by modulating PTEN/p53/PDK1/Akt/signal pathways through PTEN/p53-independent manner in HCT116 colon cancer cells. BMC Complement Altern Med. 2017;17:1–12.
Liu R, Chen Z, Hu G, Yu Z, Li Q, Liu D et al. A novel PDK1/MEK dual inhibitor induces cytoprotective autophagy via the PDK1/Akt signaling pathway in non-small cell lung cancer. Pharmaceuticals (Basel Switzerland). 2023;16(2).
Wan G, Xie W, Liu Z, Xu W, Lao Y, Huang N, et al. Hypoxia-induced MIR155 is a potent autophagy inducer by targeting multiple players in the MTOR pathway. Autophagy. 2014;10(1):70–9.
Zhang Q, Song J, Cao L, Sun M, Xu T, Yang S, et al. RNF113A targeted by miR-197 promotes proliferation and inhibits autophagy via CXCR4/CXCL12/AKT/ERK/Beclin1 axis in cervical cancer. Exp Cell Res. 2023;428(1):113632.
Li N, Guo X, Liu L, Wang L, Cheng R. Molecular mechanism of miR-204 regulates proliferation, apoptosis and autophagy of cervical cancer cells by targeting ATF2. Artif Cells Nanomed Biotechnol. 2019;47(1):2529–35.
Lu R, Yang Z, Xu G, Yu S. miR-338 modulates proliferation and autophagy by PI3K/AKT/mTOR signaling pathway in cervical cancer. Biomed Pharmacother. 2018;105:633–44.
Hansen TE, Johansen T. Following autophagy step by step. BMC Biol. 2011;9:39.
Mizushima N. Autophagy: process and function. Genes Dev. 2007;21(22):2861–73.
Ohsumi Y. Historical landmarks of autophagy research. Cell Res. 2014;24(1):9–23.
Klionsky DJ, Cregg JM, Dunn WA Jr., Emr SD, Sakai Y, Sandoval IV, et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell. 2003;5(4):539–45.
Tran E, Chow A, Goda T, Wong A, Blakely K, Rocha M, et al. Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy. Biochem Biophys Res Commun. 2013;441(4):726–31.
Tanida I, Sou YS, Ezaki J, Minematsu-Ikeguchi N, Ueno T, Kominami E. HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated protein light chain 3- and GABAA receptor-associated protein-phospholipid conjugates. J Biol Chem. 2004;279(35):36268–76.
Fujita N, Hayashi-Nishino M, Fukumoto H, Omori H, Yamamoto A, Noda T, et al. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol Biol Cell. 2008;19(11):4651–9.
Li Y, Luo Q, Yuan L, Miao C, Mu X, Xiao W, et al. JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced autophagy in MCF-7 cells. Toxicol Appl Pharmcol. 2012;263(1):21–31.
Akin D, Wang SK, Habibzadegah-Tari P, Law B, Ostrov D, Li M, et al. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014;10(11):2021–35.
Rothe K, Lin H, Lin KB, Leung A, Wang HM, Malekesmaeili M, et al. The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells. Blood. 2014;123(23):3622–34.
Nowak R, Tarasiuk J. Anthraquinone antitumour agents, doxorubicin, pirarubicin and benzoperimidine BP1, trigger caspase-3/caspase-8-dependent apoptosis of leukaemia sensitive HL60 and resistant HL60/VINC and HL60/DOX cells. Anticancer Drugs. 2012;23(4):380–92.
Liu S, Hou J, Zhang H, Wu Y, Hu M, Zhang L, et al. The evaluation of the risk factors for non-muscle invasive bladder cancer (NMIBC) recurrence after transurethral resection (TURBt) in Chinese population. PLoS ONE. 2015;10(4):e0123617.
Gu X, Jia S, Wei W, Zhang WH. Neoadjuvant chemotherapy of breast cancer with pirarubicin versus epirubicin in combination with cyclophosphamide and docetaxel. Tumour Biol J Int Soc Oncodev Biol Med. 2015;36(7):5529–35.
Wu Y, Ni Z, Yan X, Dai X, Hu C, Zheng Y, et al. Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin. Autophagy. 2016;12(7):1105–17.
Tan D, Zhou C, Han S, Hou X, Kang S, Zhang Y. MicroRNA-378 enhances migration and invasion in cervical cancer by directly targeting autophagy-related protein 12. Mol Med Rep. 2018;17(5):6319–26.
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the Beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809–20.
Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell. 2011;22(2):165–78.
Aquila S, Santoro M, Caputo A, Panno ML, Pezzi V, De Amicis F. The tumor suppressor PTEN as molecular switch node regulating cell metabolism and autophagy: implications in immune system and tumor microenvironment. Cells. 2020;9(7).
Wang W, Liu L, Tian Y. miR-19-3p targets PTEN to regulate cervical cancer cell proliferation, invasion, and autophagy. Genet Res (Camb). 2023;2023:4784500.
Yang Y, Yang Y, Yang X, Zhu H, Guo Q, Chen X, et al. Autophagy and its function in radiosensitivity. Tumor Biology. 2015;36:4079–87.
Song L, Liu S, Zhang L, Yao H, Gao F, Xu D, et al. MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1α feedback loop and the Akt-mTOR signaling pathway. Tumor Biology. 2016;37(9):12161–8.
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–79.
Hassannia B, Vandenabeele P, Berghe TV. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830–49.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–31.
Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. 2022;15(1):1–32.
Lee J-Y, Kim WK, Bae K-H, Lee SC, Lee E-W. Lipid metabolism and ferroptosis. Biology. 2021;10(3):184.
Zhang C, Liu X, Jin S, Chen Y, Guo R. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. 2022;21(1):47.
Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–92.
Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D, editors. Ferroptosis is a type of autophagy-dependent cell death. Seminars in cancer biology. Elsevier; 2020.
Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ III, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016;12(8):1425–8.
Huang T, Sun Y, Li Y, Wang T, Fu Y, Li C et al. Growth inhibition of a novel iron chelator, DpdtC, against hepatoma carcinoma cell lines partly attributed to ferritinophagy-mediated lysosomal ROS generation. Oxidative Medicine and Cellular Longevity. 2018;2018.
Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509(7498):105–9.
Zhang H, Ge Z, Wang Z, Gao Y, Wang Y, Qu X. Circular RNA RHOT1 promotes progression and inhibits ferroptosis via mir-106a-5p/STAT3 axis in breast cancer. Aging. 2021;13(6):8115–26.
Jiang Z, Zhou J, Deng J, Li L, Wang R, Han Y, et al. Emerging roles of ferroptosis-related MiRNAs in tumor metastasis. Cell Death Discovery. 2023;9(1):193.
Guo L, Zhang Q, Liu Y. The role of MicroRNAs in ferroptosis. Front Mol Biosci. 2022;9.
Dai S-M, Li F-J, Long H-Z, Zhou Z-W, Luo H-Y, Xu S-G, et al. Relationship between MiRNA and ferroptosis in tumors. Front Pharmacol. 2022;13:977062.
Lei J-Y, Li S-X, Li F, Li H, Lei Y-S. Zinc oxide nanoparticle regulates the ferroptosis, proliferation, invasion and steaminess of cervical cancer by miR-506-3p/CD164 signaling. Cancer Nanotechnol. 2022;13(1):33.
Wu P, Li C, Ye DM, Yu K, Li Y, Tang H, et al. Circular RNA circEPSTI1 accelerates cervical cancer progression via miR-375/409-3P/515-5p-SLC7A11 axis. Aging. 2021;13(3):4663–73.
Lee J, Roh JL. Targeting GPX4 in human cancer: implications of ferroptosis induction for tackling cancer resilience. Cancer Lett. 2023;559:216119.
Liu Y, Li L, Yang Z, Wen D, Hu Z. Circular RNA circACAP2 suppresses ferroptosis of cervical cancer during malignant progression by miR-193a-5p/GPX4. J Oncol. 2022;2022:5228874.
Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 2017;21(4):648–57.
Louandre C, Ezzoukhry Z, Godin C, Barbare JC, Mazière JC, Chauffert B, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to Sorafenib. Int J Cancer. 2013;133(7):1732–42.
Jia B, Li J, Song Y, Luo C. ACSL4-mediated ferroptosis and its potential role in central nervous system diseases and injuries. Int J Mol Sci. 2023;24(12):10021.
Xiaofei J, Mingqing S, Miao S, Yizhen Y, Shuang Z, Qinhua X, et al. Oleanolic acid inhibits cervical cancer Hela cell proliferation through modulation of the ACSL4 ferroptosis signaling pathway. Biochem Biophys Res Commun. 2021;545:81–8.
Wu P, Li C, mei Ye D, Yu K, Li Y, Tang H, et al. Circular RNA circEPSTI1 accelerates cervical cancer progression via miR-375/409-3P/515-5p-SLC7A11 axis. Aging. 2021;13(3):4663.
Ou R, Lu S, Wang L, Wang Y, Lv M, Li T et al. Circular RNA circLMO1 suppresses cervical cancer growth and metastasis by triggering miR-4291/ACSL4-mediated ferroptosis. Front Oncol. 2022;12.
Man SM, Kanneganti TD. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol. 2016;16(1):7–21.
Man SM, Karki R, Kanneganti TD. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017;277(1):61–75.
Jorgensen I, Miao EA. Pyroptotic cell death defends against intracellular pathogens. Immunol Rev. 2015;265(1):130–42.
Sangiuliano B, Pérez NM, Moreira DF, Belizário JE. Cell death-associated molecular-pattern molecules: inflammatory signaling and control. Mediators of inflammation. 2014;2014.
Zychlinsky A, Fitting C, Cavaillon J-M, Sansonetti PJ. Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri. J Clin Investig. 1994;94(3):1328–32.
Yu S, Zhao N, He M, Zhang K, Bi X. MiRNA-214 promotes the pyroptosis and inhibits the proliferation of cervical cancer cells via regulating the expression of NLRP3. Cell Mol Biol. 2020;66(6):59–64.
Liang T, Lu T, Jia W, Li R, Jiang M, Jiao Y, et al. Knockdown of LncRNA < Em > MALAT1 induces pyroptosis by regulating the miR–124/SIRT1 axis in cervical cancer cells. Int J Oncol. 2023;63(6):138.
Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Et Biophys Acta (BBA)-Molecular Cell Res. 2013;1833(12):3481–98.
Taddei M, Giannoni E, Fiaschi T, Chiarugi P. Anoikis: an emerging hallmark in health and diseases. J Pathol. 2012;226(2):380–93.
Fatemipour M, Nahand JS, Azar MEF, Baghi HB, Taghizadieh M, Sorayyayi S, et al. Human papillomavirus and prostate cancer: the role of viral expressed proteins in the inhibition of anoikis and induction of metastasis. Microb Pathog. 2021;152:104576.
Mak CS, Yung MM, Hui LM, Leung LL, Liang R, Chen K, et al. MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis. Mol Cancer. 2017;16:1–17.
Derouet MF, Liu G, Darling GE. MiR-145 expression accelerates esophageal adenocarcinoma progression by enhancing cell invasion and anoikis resistance. PLoS ONE. 2014;9(12):e115589.
Zhang X, Li X-f, Gu Z-p, Yang A-g, Zhang R, Li J-p, et al. A miR-124/ITGA3 axis contributes to colorectal cancer metastasis by regulating anoikis susceptibility. Biochem Biophys Res Commun. 2018;501(3):758–64.
Chen M, Liu L-x. MiR-525-5p repressed metastasis and anoikis resistance in cervical cancer via blocking UBE2C/ZEB1/2 signal axis. Dig Dis Sci. 2020;65(8):2442–51.
Xiong Y, Lu J, Fang Q, Lu Y, Xie C, Wu H, et al. UBE2C functions as a potential oncogene by enhancing cell proliferation, migration, invasion, and drug resistance in hepatocellular carcinoma cells. Biosci Rep. 2019;39(4):BSR20182384.
Bose MV, Gopal G, Selvaluxmy G, Rajkumar T. Dominant negative ubiquitin-conjugating enzyme E2C sensitizes cervical cancer cells to radiation. Int J Radiat Biol. 2012;88(9):629–34.
García-Escudero R, Martínez-Cruz AB, Santos M, Lorz C, Segrelles C, Garaulet G, et al. Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy. Mol Cancer. 2010;9(1):1–18.
Ye C, Hu Y, Wang J. MicroRNA-377 targets zinc finger E-box-binding homeobox 2 to inhibit cell proliferation and invasion of cervical cancer. Oncol Res. 2019;27(2):183.
Cheng R, Li N, Yang S, Liu L, Han S. Long non-coding RNA ZEB1-AS1 promotes cell invasion and epithelial to mesenchymal transition through inducing ZEB1 expression in cervical cancer. OncoTargets Therapy. 2018:7245–53.
Wang Y, Dong X, Hu B, Wang X-j, Wang Q, Wang W-l. The effects of Micro-429 on Inhibition of cervical cancer cells through targeting ZEB1 and CRKL. Biomed Pharmacother. 2016;80:311–21.
Fenner A. Identifying undifferentiated spermatogonia in patients with Klinefelter syndrome. Nat Reviews Urol. 2022;19(11):634.
Jin D, Guo J, Wu Y, Du J, Wang X, An J, et al. UBE2C, directly targeted by miR-548e-5p, increases the cellular growth and invasive abilities of cancer cells interacting with the EMT marker protein zinc finger E-box binding homeobox 1/2 in NSCLC. Theranostics. 2019;9(7):2036.
Chen M, Liu L-x. MiR-525-5p repressed metastasis and Anoikis resistance in cervical cancer via blocking UBE2C/ZEB1/2 signal axis. Dig Dis Sci. 2020;65:2442–51.
Gambari R, Brognara E, Spandidos DA, Fabbri E. Targeting OncomiRNAs and mimicking tumor suppressor MiRNAs: Νew trends in the development of MiRNA therapeutic strategies in oncology (Review). Int J Oncol. 2016;49(1):5–32.
Mohamadi S, Mehrasa P, Mehramuz B, Kobravi S, Taghizadieh M, Salmaninejad A et al. The tumor microenvironment’s gambit: Exosomal pawns on the board of head and neck cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2024;1879(6):189189.
Reda El Sayed S, Cristante J, Guyon L, Denis J, Chabre O, Cherradi N. MicroRNA therapeutics in cancer: current advances and challenges. Cancers (Basel). 2021;13(11).
Zhou WY, Chen JC, Jiao TT, Hui N, Qi X. MicroRNA-181 targets Yin Yang 1 expression and inhibits cervical cancer progression. Mol Med Rep. 2015;11(6):4541–6.
Peralta-Zaragoza O, Deas J, Meneses-Acosta A, De la O-Gómez F, Fernández-Tilapa G, Gómez-Cerón C, et al. Relevance of miR-21 in regulation of tumor suppressor gene PTEN in human cervical cancer cells. BMC Cancer. 2016;16(1):215.
Liu L, Rotondo JC, Tian Y, Wang W. miR-19-3p targets PTEN to regulate cervical cancer cell proliferation, invasion, and autophagy. Genet Res. 2024;2023:e20.
Peng X, Zhang Y, Gao J, Cai C. MiR-1258 promotes the apoptosis of cervical cancer cells by regulating the E2F1/P53 signaling pathway. Exp Mol Pathol. 2020;114:104368.
Jiang L, Shi S, Shi Q, Zhang H, Xia Y, Zhong T. MicroRNA-519d-3p inhibits proliferation and promotes apoptosis by targeting HIF-2α in cervical cancer under hypoxic conditions. Oncol Res. 2018;26(7):1055–62.
Esfandyari YB, Doustvandi MA, Amini M, Baradaran B, Zaer SJ, Mozammel N, et al. MicroRNA-143 sensitizes cervical cancer cells to cisplatin: a promising anticancer combination therapy. Reproductive Sci. 2021;28(7):2036–49.
Liu S, Pan X, Yang Q, Wen L, Jiang Y, Zhao Y, et al. MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis. Oncol Rep. 2015;33(6):2853–62.
Yu M, Xu B, Yang H, Xue S, Zhang R, Zhang H, et al. MicroRNA-218 regulates the chemo-sensitivity of cervical cancer cells through targeting survivin. Cancer Manage Res. 2019;11(null):6511–9.
Zhang Q, Lv R, Guo W, Li X. microRNA-802 inhibits cell proliferation and induces apoptosis in human cervical cancer by targeting serine/arginine‐rich splicing factor 9. J Cell Biochem. 2019;120(6):10370–9.
Sun J, Ji J, Huo G, Song Q, Zhang X. miR-182 induces cervical cancer cell apoptosis through inhibiting the expression of DNMT3a. Int J Clin Exp Pathol. 2015;8(5):4755–63.
Cao Z, Zhang G, Xie C, Zhou Y. MiR-34b regulates cervical cancer cell proliferation and apoptosis. Artif Cells Nanomed Biotechnol. 2019;47(1):2042–7.
Lin L, Xin B, Jiang T, Wang X-l, Yang H, Shi T-m. Long non-coding RNA LINC00460 promotes proliferation and inhibits apoptosis of cervical cancer cells by targeting microRNA-503-5p. Mol Cell Biochem. 2020;475(1):1–13.
Chen X, Cao R, Liu H, Zhang T, Yuan X, Xu S. MicroRNA–15a–5p–targeting oncogene YAP1 inhibits cell viability and induces cell apoptosis in cervical cancer cells Retraction in /10.3892/ijmm.2024.5348. Int J Mol Med. 2020;46(4):1301–10.
Cui F, Li X, Zhu X, Huang L, Huang Y, Mao C, et al. MiR-125b inhibits tumor growth and promotes apoptosis of cervical cancer cells by targeting phosphoinositide 3-kinase catalytic subunit delta. Cell Physiol Biochem. 2012;30(5):1310–8.
Lai X, Cheng X, Hu L. MicroRNA 421 induces apoptosis of c-33a cervical cancer cells via down-regulation of Bcl-xL. Genet Mol Res 2016;15(4).
Liu S, Zhang P, Chen Z, Liu M, Li X, Tang H. MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS Lett. 2013;587(14):2247–53.
Xu J, Zhu W, Chen L, Liu L. MicroRNA–433 inhibits cell growth and induces apoptosis in human cervical cancer through PI3K/AKT signaling by targeting FAK. Oncol Rep. 2018;40(6):3469–78.
Li GC, Cao XY, Li YN, Qiu YY, Li YN, Liu XJ, et al. MicroRNA-374b inhibits cervical cancer cell proliferation and induces apoptosis through the p38/ERK signaling pathway by binding to JAM‐2. J Cell Physiol. 2018;233(9):7379–90.
Lin C, Huang F, Shen G, Yiming A. MicroRNA-101 regulates the viability and invasion of cervical cancer cells. Int J Clin Exp Pathol. 2015;8(9):10148–55.
Huang F, Lin C, Shi Y-H, Kuerban G. MicroRNA-101 inhibits cell proliferation, invasion, and promotes apoptosis by regulating cyclooxygenase-2 in Hela cervical carcinoma cells. Asian Pac J Cancer Prev. 2013;14(10):5915–20.
Ma J, Zhang F, Sun P. miR-140-3p impedes the proliferation of human cervical cancer cells by targeting RRM2 to induce cell-cycle arrest and early apoptosis. Bioorg Med Chem. 2020;28(3):115283.
Chen X, Xiong D, Ye L, Wang K, Huang L, Mei S, et al. Up-regulated LncRNA XIST contributes to progression of cervical cancer via regulating miR-140-5p and ORC1. Cancer Cell Int. 2019;19(1):45.
Wei Q, Li YX, Liu M, Li X, Tang H. MiR-17‐5p targets TP53INP1 and regulates cell proliferation and apoptosis of cervical cancer cells. IUBMB Life. 2012;64(8):697–704.
Mou Z, Xu X, Dong M, Xu J. MicroRNA-148b acts as a tumor suppressor in cervical cancer by inducing G1/S-Phase cell cycle arrest and apoptosis in a Caspase-3-Dependent manner. Med Sci Monit Int Med J Exp Clin Res. 2016;22:2809–15.
He L, Wang J, Chang D, Lv D, Li H, Feng H. Effect of miRNA-200b on the proliferation and apoptosis of cervical cancer cells by targeting RhoA. Open Med. 2020;15(1):1019–27.
Wu X, Lei J, Zhou B, Sun Q, Gao Y, Shi F, et al. MiR-628–5p inhibits cervical carcinoma proliferation and promotes apoptosis by targeting VEGF. Am J Med Sci. 2021;361(4):499–508.
Zou X, Zhu C, Zhang L, Zhang Y, Fu F, Chen Y, et al. MicroRNA-708 suppresses cell proliferation and enhances chemosensitivity of cervical cancer cells to cDDP by negatively targeting timeless. OncoTargets Therapy. 2020;13(null):225–35.
Chuang P-C, Chen P-T, Wang C-C, Su W-H, Chen Y-H, Huang E-Y. MicroRNA-29a manifests multifaceted features to intensify radiosensitivity, escalate apoptosis, and revoke cell migration for palliating Radioresistance-Enhanced cervical cancer progression. Int J Mol Sci. 2022;23(10):5524.
Gong Y, Wan J-H, Zou W, Lian G-Y, Qin J-L, Wang Q-M. MiR-29a inhibits invasion and metastasis of cervical cancer via modulating methylation of tumor suppressor SOCS1. Future Oncol. 2019;15(15):1729–44.
Luo M, Shen D, Zhou X, Chen X, Wang W. MicroRNA-497 is a potential prognostic marker in human cervical cancer and functions as a tumor suppressor by targeting the insulin-like growth factor 1 receptor. Surgery. 2013;153(6):836–47.
Guo Q, Dong B, Nan F, Guan D, Zhang Y. 5-Aminolevulinic acid photodynamic therapy in human cervical cancer via the activation of microRNA-143 and suppression of the Bcl-2/Bax signaling pathway. Mol Med Rep. 2016;14(1):544–50.
Li M, Xiao Y, Liu M, Ning Q, Xiang Z, Zheng X, et al. MiR-26a-5p regulates proliferation, apoptosis, migration and invasion via inhibiting hydroxysteroid dehydrogenase like-2 in cervical cancer cell. BMC Cancer. 2022;22(1):876.
Huang Y, Luo F. Elevated microRNA-130b‐5p or silenced ELK1 inhibits self‐renewal ability, proliferation, migration, and invasion abilities, and promotes apoptosis of cervical cancer stem cells. IUBMB Life. 2021;73(1):118–29.
Jin Y, Zhou X, Yao X, Zhang Z, Cui M, Lin Y. MicroRNA-612 inhibits cervical cancer progression by targeting NOB1. J Cell Mol Med. 2020;24(5):3149–56.
Yu X, Zhao W, Yang X, Wang Z, Hao M. miR-375 affects the proliferation, invasion, and apoptosis of HPV16-positive human cervical cancer cells by targeting IGF-1R. Int J Gynecol Cancer. 2016;26(5):851–8.
Huang P, Xi J, Liu S. MiR-139-3p induces cell apoptosis and inhibits metastasis of cervical cancer by targeting NOB1. Biomed Pharmacother. 2016;83:850–6.
Hua F-F, Liu S-S, Zhu L-H, Wang Y-H, Liang X, Ma N et al. MiRNA-338-3p regulates cervical cancer cells proliferation by targeting MACC1 through MAPK signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(23).
Cao X-M. Role of miR-337-3p and its target Rap1A in modulating proliferation, invasion, migration and apoptosis of cervical cancer cells. Cancer Biomarkers. 2019;24(3):257–67.
Liu C, Wang J, Hu Y, Xie H, Liu M, Tang H. Upregulation of Kazrin F by miR-186 suppresses apoptosis but promotes epithelial-mesenchymal transition to contribute to malignancy in human cervical cancer cells. Chin J Cancer Res = Chung-kuo Yen Cheng Yen Chiu. 2017;29(1):45–56.
Wen C-X, Tian H-L, Chen E, Liu J-F, Liu X-X. MiRNA-873-5p acts as a potential novel biomarker and promotes cervical cancer progression by regulating ZEB1 via Notch signaling pathway. Dose-Response. 2021;19(1):15593258211001255.
Tian Y, Luo Y, Wang J. MicroRNA-425 induces apoptosis and suppresses migration and invasion of human cervical cancer cells by targeting RAB2B. Int J ImmunoPathol Pharmacol. 2021;35:20587384211016131.
Cong J, Liu R, Wang X, Jiang H, Zhang Y. MiR-634 decreases cell proliferation and induces apoptosis by targeting mTOR signaling pathway in cervical cancer cells. Artif Cells Nanomed Biotechnol. 2016;44(7):1694–701.
Wang G, Lu Y, Di S, Xie M, Jing F, Dai X. miR–99a–5p inhibits Glycolysis and induces cell apoptosis in cervical cancer by targeting RRAGD. Oncol Lett. 2022;24(1):228.
Ye C, Sun N-x, Ma Y, Zhao Q, Zhang Q, Xu C, et al. MicroRNA-145 contributes to enhancing radiosensitivity of cervical cancer cells. FEBS Lett. 2015;589(6):702–9.
Yan S, Li X, Jin Q, Yuan J. MicroRNA–145 sensitizes cervical cancer cells to low–dose irradiation by downregulating OCT4 expression. Exp Ther Med. 2016;12(5):3130–6.
Wang J, Chen S. RACK1 promotes miR-302b/c/d-3p expression and inhibits CCNO expression to induce cell apoptosis in cervical squamous cell carcinoma. Cancer Cell Int. 2020;20(1):385.
Liu X, Gan L, Zhang J. miR-543 inhibites cervical cancer growth and metastasis by targeting TRPM7. Chemico-Biol Interact. 2019;302:83–92.
Li BH, Zhou JS, Ye F, Cheng XD, Zhou CY, Lu WG, et al. Reduced miR-100 expression in cervical cancer and precursors and its carcinogenic effect through targeting PLK1 protein. Eur J Cancer. 2011;47(14):2166–74.
Zhang J, Li S, Yan Q, Chen X, Yang Y, Liu X, et al. Interferon-β induced microRNA-129-5p Down-Regulates HPV-18 E6 and E7 viral gene expression by targeting SP1 in cervical cancer cells. PLoS ONE. 2013;8(12):e81366.
Wang JM, Ju BH, Pan CJ, Gu Y, Li MQ, Sun L, et al. MiR-214 inhibits cell migration, invasion and promotes the drug sensitivity in human cervical cancer by targeting FOXM1. Am J Translational Res. 2017;9(8):3541–57.
Wu T, Chen X, Peng R, Liu H, Yin P, Peng H, et al. Let–7a suppresses cell proliferation via the TGF–β/SMAD signaling pathway in cervical cancer. Oncol Rep. 2016;36(6):3275–82.
Wang Y, Li X, Wang S, Song Z, Bao Y, Zheng L, et al. miR-3929 inhibits proliferation and promotes apoptosis by downregulating Cripto-1 expression in cervical cancer cells. Cytogenet Genome Res. 2021;161(8–9):425–36.
Chen J, Li G. MiR-1284 enhances sensitivity of cervical cancer cells to cisplatin via downregulating HMGB1. Biomed Pharmacother. 2018;107:997–1003.
Zhang L, Lai Y, Sun Y, Xu B, Qiang X, Zhou X, et al. HPV16 E6 regulates the proliferation, invasion, and apoptosis of cervical cancer cells by downregulating miR-504. Translational cancer Res. 2020;9(12):7588–95.
Wongjampa W, Ekalaksananan T, Chopjitt P, Chuerduangphui J, Kleebkaow P, Patarapadungkit N, et al. Suppression of miR-22, a tumor suppressor in cervical cancer, by human papillomavirus 16 E6 via a p53/miR-22/HDAC6 pathway. PLoS ONE. 2018;13(10):e0206644.
Xu J, Ma X, Yang H, Zhang J, Cai G, Yao N. MiR-509-3p induces apoptosis and affects the chemosensitivity of cervical cancer cells by targeting the RAC1/PAK1/LIMK1/Cofilin pathway. Chem Pharm Bull. 2021;69(4):325–32.
Song Y, Guo Q, Gao S, Hua K. miR-454-3p promotes proliferation and induces apoptosis in human cervical cancer cells by targeting TRIM3. Biochem Biophys Res Commun. 2019;516(3):872–9.
Zhang Y, Yang Y, Liu R, Meng Y, Tian G, Cao Q. Downregulation of microRNA–425–5p suppresses cervical cancer tumorigenesis by targeting AIFM1. Exp Ther Med. 2019;17(5):4032–8.
Zhang H, Chen R, Shao J. MicroRNA-96-5p facilitates the viability, migration, and invasion and suppresses the apoptosis of cervical cancer cells bynegatively modulating SFRP4. Technol Cancer Res Treat. 2020;19:1533033820934132.
Liu F, Zhang S, Zhao Z, Mao X, Huang J, Wu Z, et al. MicroRNA-27b up-regulated by human papillomavirus 16 E7 promotes proliferation and suppresses apoptosis by targeting polo-like kinase2 in cervical cancer. Oncotarget. 2016;7(15):19666–79.
Wang M, Wang X, Liu W. MicroRNA–130a–3p promotes the proliferation and inhibits the apoptosis of cervical cancer cells via negative regulation of RUNX3. Mol Med Rep. 2020;22(4):2990–3000.
Zhang H, Zhang Z, Wang S, Zhang S, Bi J. The mechanisms involved in miR-9 regulated apoptosis in cervical cancer by targeting FOXO3. Biomed Pharmacother. 2018;102:626–32.
Li J-H, Xiao X, Zhang Y-N, Wang Y-M, Feng L-M, Wu Y-M, et al. MicroRNA miR-886-5p inhibits apoptosis by down-regulating Bax expression in human cervical carcinoma cells. Gynecol Oncol. 2011;120(1):145–51.
Chen Y, Song Y, Mi Y, Jin H, Cao J, Li H, et al. microRNA-499a promotes the progression and chemoresistance of cervical cancer cells by targeting SOX6. Apoptosis. 2020;25(3):205–16.
Lv KT, Liu Z, Feng J, Zhao W, Hao T, Ding WY, et al. MiR-22-3p regulates cell proliferation and inhibits cell apoptosis through targeting the eIF4EBP3 gene in human cervical squamous carcinoma cells. Int J Med Sci. 2018;15(2):142–52.
Lao G, Liu P, Wu Q, Zhang W, Liu Y, Yang L, et al. Mir-155 promotes cervical cancer cell proliferation through suppression of its target gene LKB1. Tumor Biology. 2014;35(12):11933–8.
Peng L-n, Shi W-t, Feng H-r, Wei C-y. Yin Q-n. Effect of miR-301a/PTEN pathway on the proliferation and apoptosis of cervical cancer. Innate Immun. 2019;25(4):217–23.
Phuah NH, Azmi MN, Awang K, Nagoor NH. Suppression of microRNA-629 enhances sensitivity of cervical cancer cells to 1′S-1′-acetoxychavicol acetate via regulating RSU1. OncoTargets Therapy. 2017;10(null):1695–705.
Pan X, Cao Y-M, Liu J-H, Ding J, Xie X-Y, Cao P-G. MEG3 induces cervical carcinoma cells’ apoptosis through Endoplasmic reticulum stress by miR-7-5p/STC1 axis. Cancer Biother Radiopharm. 2021;36(6):501–10.
Song L, Liu S, Zhang L, Yao H, Gao F, Xu D, et al. MiR-21 modulates radiosensitivity of cervical cancer through inhibiting autophagy via the PTEN/Akt/HIF-1α feedback loop and the Akt-mTOR signaling pathway. Tumor Biology. 2016;37:12161–8.
Wei Y-Q, Jiao X-L, Zhang S-Y, Xu Y, Li S, Kong B-H. MiR-9-5p could promote angiogenesis and radiosensitivity in cervical cancer by targeting SOCS5. Eur Rev Med Pharmacol Sci. 2019;23(17).
Cheng Y, Chen G, Hu M, Huang J, Li B, Zhou L, et al. Has-miR-30a regulates autophagic activity in cervical cancer upon hydroxycamptothecin exposure. Biomed Pharmacother. 2015;75:67–74.
Duan P, Cheng J, Mao R, Wang R, Jin Y, Li C. Icariin-mediated miR-875-5p inhibits autophagy and epithelial-mesenchymal transition by regulation of MDM4 in cervical cancer. J Biomed Nanotechnol. 2022;18(12):2708–20.
Fang W, Shu S, Yongmei L, Endong Z, Lirong Y, Bei S. miR-224-3p inhibits autophagy in cervical cancer cells by targeting FIP200. Sci Rep. 2016;6(1):33229.
Cui X, Wang X, Zhou X, Jia J, Chen H, Zhao W. miR-106a regulates cell proliferation and autophagy by targeting LKB1 in HPV-16-Associated cervical cancer. Mol Cancer Res. 2020;18(8):1129–41.
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Taghizadieh, M., Kalantari, M., Bakhshali, R. et al. To be or not to be: navigating the influence of MicroRNAs on cervical cancer cell death. Cancer Cell Int 25, 153 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03786-y
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DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03786-y