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Molecular mechanisms of miR-192 in cancer: a biomarker and therapeutic target

Cancer Cell International volume 25, Article number: 94 (2025) Cite this article

Abstract

Cancer remains a major global health challenge due to its rising prevalence and high mortality rates. The field of microRNAs (miRNAs) has made significant progress in the understanding of tumorigenesis and has broadened our knowledge of their targeting, especially in cancer therapy. miRNAs, a class of small non-coding RNAs, participate in post-transcriptional gene regulation by translational inhibition or mRNA degradation. Among these, microRNA-192 (miR-192) is located on human chromosome 11q13.1, and is highly correlated with the occurrence and development of various human cancers. Dysregulation of miR-192 has been extensively studied in various pathological processes, including tumorigenesis, making it a valuable biomarker for cancer diagnosis and prognosis. The functional role of miR-192 varies across cancer types, acting as either a tumor suppressor or as an oncogene through the modulation of multiple gene expressions and downstream signaling pathways. However, the roles of miR-192 in cancer appear inconsistent across types, with current research often focused on specific genes or pathways, limiting insight into its broader impact on cellular signaling networks. Therefore, this review aims to provide a comprehensive overview of miR-192 research. The paper reviews differences in miR-192 expression in cancer and systematically summarizes the role of miR-192 in cancers. The review further explores the complex roles of miR-192 in various pathological processes, emphasizing its regulatory pathways, interaction networks, and association with tumor progression. This review also illustrates the clinical application of miR-192 as a diagnostic and prognostic biomarker for non-invasive cancer detection, as it is consistently present in both serum and exosomes. A comprehensive summary and analysis of the relationship between miR-192 and various cancers may provide valuable insights, potentially guiding novel approaches in clinical diagnosis, therapeutic strategies, and foundational cancer research.

Background

Cancer poses a significant global public health challenge due to its increasing prevalence and high mortality rate. There remains an urgent need to identify novel diagnostic markers and therapeutic targets to improve patient outcomes [1, 2]. The exploration of molecular targets, particularly in the field of non-coding RNAs, has highlighted miRNAs as promising candidates due to their extensive regulatory roles in various pathological processes, including tumorigenesis [3]. Essentially, miRNAs are small non-coding RNA molecules (around 22 nucleotides) that regulate gene expression at the post-transcriptional level in a wide range of biological contexts [4, 5].

Furthermore, miRNAs are distinguished by a “seed” sequence, typically 7–8 nucleotides long, which binds to the 3'-untranslated regions (3'-UTRs) of target mRNAs, influencing mRNA stability and translation. The human miR-192 sequence, specifically the 24-CUGACCUAUGAAUUGACAGCC-44 seed (https://www.mirbase.org/search.shtml), is located on the human chromosome 11q13.1 [6]. miRNA biogenesis is a multi-step process involving transcription of primary miRNAs (pri-miRNAs) by RNA polymerase II or III, processed by the Drosha-DiGeorge Syndrome Critical Region 8 (Drosha-DGCR8) complex into precursor miRNAs (pre-miRNAs), with further maturation in the cytoplasm by Dicer to form the mature miRNA duplex [7,8,9,10,11]. For miR-192, the guide strand (miR-192-5p, originating from the 5’ side of the pre-miRNA) binds to the argonaut protein (AGO) to form the miRNA-induced silencing complex (RISC). Meanwhile, the passenger strand (miR-192-3p, the complementary 3’ strand) is usually degraded. Both miR-192-3p and miR-192-5p, however, target genes implicated in oncogenic processes, affecting cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and drug resistance [12]. Both miR-192-3p and miR-192-5p target specific genes involved in cancer, thereby influencing key cellular processes, including cell proliferation, migration, invasion, EMT, angiogenesis and drug resistance.

miR-192 is aberrantly expressed across multiple cancer types, where it exerts either oncogenic or oncostatic effects, making it a promising target in cancer therapy. This dual role indicates its complex and context-dependent impact on cancer biology. Despite the growing evidence of miR-192's involvement in cancer, its functional roles appear to vary across different cancer types, and the consistency of these roles remains uncertain. Current research focuses on isolated target genes or specific signaling pathways, which limits our understanding of miR-192’s broader influence within the intricate network of cellular signaling pathways involved in cancer progression.

In understanding miR-192’s role in cancer, this review consolidates current insights into the aberrant expression, multifaceted functions, and complex regulatory mechanisms of miR-192 across various cancers. By highlighting its upstream regulators, downstream targets, and associated signaling pathways, The review aims to provide a comprehensive understanding of miR-192’s role in cancer progression. Additionally, its potential clinical applications as a diagnostic and prognostic biomarker are highlighted.

Expression of miR-192 in various cancers

miR-192 exhibits dynamic expression patterns that vary across tissues. It is highly expressed in certain normal tissues, such as the liver, kidney, intestine, and epithelial tissues, while its expression may be minimal in others. Notably, miR-192 expression is often dysregulated in cancers, where it undergoes significant alterations. A summary of miR-192 expression patterns in different cancers is provided in Table 1.

Table 1 The expression of miR-192 in cancers
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Upregulation of miR-192 in cancers

Several investigations have found elevated levels of miR-192 in various cancers, including cholangiocarcinoma, cervical cancer, hypoxic head and neck squamous cell carcinoma (HNSCC), and nasopharyngeal carcinoma. Specifically, studies have observed increased levels of miR-192-5p in cholangiocarcinoma tissues [12, 13], cell lines [12], urine [14], and serum of cholangiocarcinoma patients [15]. Similarly, elevated miR-192-5p levels have been found in cervical cancer tissues [16], hypoxic small extracellular vesicles (sEVs) from HNSCC [17], and nasopharyngeal carcinoma tissues and cells [18].

These findings emphasize the overexpression of miR-192 across various cancer types, indicating its potential role in cancer progression.

Downregulation of miR-192 in cancers

The downregulation of miR-192 has been consistently reported across multiple cancer types, including breast cancer, glioma, medulloblastoma, colorectal cancer, bladder cancer, pediatric acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), papillary thyroid carcinoma (PTC), osteosarcoma, and epithelial ovarian cancer (EOC) (Table 1). Numerous studies have documented decreased miR-192 expression in breast cancer tissues and cells [19, 20], with even lower levels observed in doxorubicin (DOX)-resistant breast cancer cell lines [21]. Significant reductions in miR-192 levels have also been observed in tissues and cells of glioma [22, 23], medulloblastoma [24], colorectal cancer [25,26,27,28,29,30,31], bladder Cancer [32], PTC [33], osteosarcoma [34,35,36,37,38], nephroblastoma subtypes [39], and endometrial cancer tissues [40], as well as in exosomes derived from tumor-associated macrophages (TAMs) [41].

Furthermore, miR-192 downregulation has been reported in various biofluids, including the serum of colon cancer [42, 43] and AML [44, 45] patients, the urine of bladder cancer patients [46] and the peripheral blood mononuclear cells (PBMCs) from CLL cases [47]. Interestingly, one study reported no difference in miR-192-5p expression in both colon cancer tissues and serum samples [43], suggesting further investigation to elucidate its role in this context.

Variable expression of miR-192 in cancers

Certainly, the expression profile of miR-192 exhibits paradoxical patterns across different cancers, particularly in esophageal cancer, EOC, gastric cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer, and prostate cancer.

miR-192 expression increases in the plasma of esophageal cancer patients [48] and in the tissues and cells of esophageal squamous cell carcinoma (ESCC) [49]. Additionally, miR-192 expression decreases post-therapy [50]. Notably, one study found that miR-192-5p expression rises following neoadjuvant chemotherapy and cisplatin treatment [48], suggesting its role in enhancing sensitivity to cisplatin, though it may also contribute to esophageal cancer progression.

In EOC, miR-192 has been shown to be highly expressed in ovarian mucinous carcinoma tissues [51] but reduced in plasma exosomes of individuals with EOC [52]. This indicates that cancer development involves diverse types and phases, each characterized by distinct molecular features that contribute to the variation in miR-192 expression. Even within the same cancer, distinct cell types can exhibit multiple miR-192 expression patterns. For instance, miR-192 expression is higher in the serum of gastric cancer patients with distant metastasis compared to those without metastasis [67]. Additionally, studies reported both upregulation [53,54,55,56,57,58] and downregulation [43, 59, 60] of miR-192 in gastric cancer tissues, cell lines, and serum from gastric cancer patients, which indicates significant variability in its expression.

A similar pattern of discrepancies is observed in hepatocellular carcinoma and pancreatic cancer. In hepatocellular carcinoma, miR-192 is generally downregulated in tissues [61,62,63,64] and cell lines [62, 65, 66], but upregulated in patients’ serum exosomes and specific cell populations resembling cancer stem cells (CSC) [67]. In pancreatic cancer, elevated expression of miR-192 has been observed in the serum of patients [68], as well as in serum exosomes, tissues, and pancreatic ductal adenocarcinoma (PDAC) cells [69, 70]. However, it is downregulated in PDAC tissues and gemcitabine-resistant cells [69]. These variations can be attributed to the diverse sources of circulating miRNAs, which include tumor cells and PBMCs. miRNAs are encapsulated within extracellular vesicles or bound to protein complexes, providing protection from degradation and explaining the discrepancies in miR-192 levels between tissues and circulation. Furthermore, the differing half-lives of miRNAs in blood versus tissues, influenced by factors such as RNase activity, contribute to these variations.

In lung cancer, miR-192 displays diminished expression in tissues [71], serum of patients with bone metastasis [72], and bronchial lavage fluid [73]. However, cellular studies present conflicting results, with some showing decreased expression [72, 73], while others report increased expression [74,75,76], particularly higher in cisplatin-resistant lung carcinoma cells [77, 78]. In prostate cancer, data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) show elevated miR-192 expression in tissues [79], whereas cell studies on cultured cells report downregulation [80, 81]. Notably, cell lines often deviate from the characteristics of the original tumor tissues due to accumulated mutations over time, which can lead to discrepancies in miRNA expression. Additionally, the tumor microenvironment and various cell types present in tumor tissues further influence miR-192 levels, which may not be fully represented by in vitro studies.

Therefore, miR-192 shows variable expression across different cancers, influenced by factors such as tumor stage, metastasis, drug resistance, and the tumor microenvironment. These expression differences highlight its potential as a biomarker for cancer diagnosis, prognosis, and treatment monitoring. However, further research is needed to fully elucidate its role and mechanisms in different cancer types.

The role of miR-192 in cancer progression

The dysfunction of miR-192 is implicated in several key processes of tumorigenesis, including cancer cell proliferation, apoptosis, migration, invasion, metastasis, EMT, and angiogenesis. miR-192 exerts distinct roles across various tumors by regulating multiple target genes. Its primary role in most cancers is to prevent tumor development, However, in gastric cancer, it predominantly exhibits oncogenic properties (Fig. 1). The tumor-suppressive effect of miR-192 on specific target genes, such as MYC, XIAP, and ZEB2, is consistent across various cancers (Fig. 1). However, miR-192 can exhibit dual effects when targeting the same gene in different cancers, such as BCL-2 and RB1 (Fig. 1). Therefore, the distinct functions of miR-192 can be further explored by targeting specific genes in distinct types of cancer (Fig. 1).

Fig. 1
figure 1

Pathological Processes Involving miR-192 in Tumorigenesis. This figure illustrates the dual roles of miR-192 across cancer types, where it functions either as a tumor suppressor or an oncogene by targeting specific genes

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Gastric cancer

Most studies have found that miR-192 functions as an oncogene in gastric cancer. Specifically, miR-192 has been observed to enhance cell proliferation and migration by downregulating ALCAM [56], APC [55], and Rab11-FIP2 [82]. In addition, it promotes EMT and Treg cell differentiation by suppressing RB1 [53]. Its role in decreasing SET domain containing lysine methyltransferase 8 (SET8) expression prevents cellular senescence and apoptosis, thus promoting gastric cancer initiation and progression [54].

However, one specific study identifies miR-192-5p as a tumor suppressor, reversing cisplatin resistance in gastric cancer cells by targeting ERCC3 and ERCC4 [60].

Lung cancer

Lung cancer remains consistently ranked as the most diagnosed cancer and was the primary cause of cancer-related deaths by 2022 [1, 2]. miR-192 plays a complex role in lung cancer, acting both as a tumor suppressor and an oncogene. It induces cell cycle arrest by downregulating CCNB1 and MYC [83, 84]. It also inhibits proliferation and EMT while promoting apoptosis through RB1 downregulation in non-small-cell lung cancer (NSCLC) [71, 85], and has been found to target TRIM44 to curb cancer cell proliferation, migration, and invasion [54]. Moreover, miR-192-5p exerts pro-apoptotic effects by interacting with XIAP in NSCLC cells [56].

Additionally, miR-192 may contribute to lung cancer progression by promoting cisplatin resistance and inhibiting apoptosis through the downregulation of NKRF [77] or BIM [78]. Additionally, miR-192 regulates chemoresistance to combined gemcitabine and cisplatin chemotherapy by targeting BCL-2 in human adenocarcinoma lung cancer A549 cells [74].

Liver cancer

Primarily, miR-192 primarily functions as a tumor suppressor in liver cancer. Studies have shown that miR-192-5p triggers apoptosis and hampers cell growth, migration, and invasion in hepatocellular carcinoma by downregulating XIAP [86]. Additionally, miR-192 targets TRIM25 to inhibit proliferation and migration in hepatitis B virus-related hepatocellular carcinoma [61], and targets SLC39A6 to reduce tumor metastasis in hepatocellular carcinoma cells [62]. Upregulation of miR-192-5p has also been associated with the activation of autophagy and apoptosis via CYR61 in hepatocellular carcinoma [66].

Interestingly, the absence of miR-192-5p has been observed to promote stemness features in CSC-positive hepatocellular carcinoma cells by upregulating MYC, PFKFB3, GLUT1 [87], and PABPC4 [65]. Another study demonstrated that ZEB2, both a target of miR-192 and an EMT activator, increases in the absence of miR-192, thereby promoting EMT and invasion [88].

However, a few studies indicate the oncogenic role of miR-192. For instance, miR-192-5p has been implicated in targeting SEMA3A, potentially enhancing cell proliferation, angiogenesis, and metastasis [67].

Colorectal cancer

Colorectal cancer research has identified miR-192-5p as a tumor suppressor, playing a crucial role in inhibiting cancer progression. In particular, miR-192-5p modulates apoptosis by targeting EIF5A2 [30], RAB2A [26], and BMPR2 [25], while also inhibiting cell proliferation, migration, and invasion. Additionally, its interaction with SRPX2 has been shown to suppress colorectal cancer development by inhibiting proliferation and enhancing glycolysis [28]. It also promotes apoptosis by downregulating BCL-2 [29], and inhibits EMT by targeting ZEB2 [29] and NID1 [89]. In addition, it hinders angiogenesis by regulating VEGFA [29] in colorectal cancer. Another study demonstrated that miR-192 sensitizes HCT-116 cells to methotrexate (MTX) by regulating DHFR, suggesting a novel therapeutic approach to the treatment of patients with colon cancer [90].

Breast cancer

Breast cancer is the most commonly diagnosed cancer among women and is the leading cause of cancer-related deaths globally [2]. In breast cancer, miR-192 exhibits tumor-suppressive effects. Specifically, miR-192 inhibits proliferation and promotes apoptosis by targeting CAV1 [19]. Additionally, miR-192-5p sensitizes breast cancer cells to DOX and regulates cell growth by targeting PPIA, highlighting its potential as a therapeutic target [21]. A mechanistic study further demonstrated that miR-192 induces cell cycle arrest by downregulating RB1 [20]. In triple-negative breast cancer (TNBC), miR-192 also acts as a tumor suppressor by increasing apoptosis and inhibiting both proliferation and migration, with ARHGAP19 identified as a novel target gene of miR-192 [91].

Cervical cancer

Cervical cancer ranked fourth for both incidence and mortality among women by 2022 [2]. In cervical cancer, miR-192-5p exerts a tumor-suppressive function by inhibiting proliferation, migration, and invasion through direct targeting of TRPM7 [92]. Silencing miR-192-5p has the opposite effect, promoting these oncogenic processes by regulating ALX1 [40] and RB1 [93]. Furthermore, miR-192-5p derived from TAMs exosomes has been observed to suppress EMT and promote apoptosis by targeting IRAK1 in endometrial cancer [41].

Osteosarcoma

miR-192 plays a tumor-suppressive role in osteosarcoma by regulating cell proliferation, apoptosis, migration, and invasion. It achieves these effects by selectively targeting specific genes, including TCF7 [37], MMP11 [35], and USP1 [36]. Additionally, another study demonstrated that miR-192 inhibits osteosarcoma cell proliferation and induces apoptosis by interacting with XIAP [34]. Additionally, miR-192 has been shown to enhance the sensitivity of MG-63 cells to MTX [94] and to improve the sensitivity to cisplatin by targeting USP1 [36].

Others

In nasopharyngeal carcinoma, miR-192 promotes tumor progression through RB1 inhibition [18], while in HNSCC, it enhances malignancy via CAV1 downregulation [17]. Similarly, miR-192 contributes to neuroblastoma development by targeting Dicer1 [95].

Conversely, miR-192 serves a tumor-suppressive function in various cancers. In PTC, it reduces malignancy by regulating SH3RF3, affecting migration, invasion, and EMT [33]. In bladder cancer, miR-192 inhibits tumor growth [32, 96], by downregulating the transcription factor Yin Yang 1 linked to cancer cell proliferation [32], and is also associated with gemcitabine resistance in bladder cancer [97]. In multiple myeloma, miR-192 acts as a tumor suppressor by targeting IL-17Rs [98], and bioinformatic analyses suggest it connects with the bone marrow microenvironment by interacting with CDKN2A, influencing tumor progression [99]. In AML, miR-192 suppresses cancer progression by targeting CCNT2 [45], ULK1 [100], and ZBTB20 [101], with additional anti-tumor effects linked to modulation of the WNT signaling pathway [102].

In renal cancers, miR-192 acts as a tumor suppressor by targeting MDM2, ZEB2, and TYMS in renal cell carcinoma, thereby reducing migration and invasion [103]. In nephroblastoma, it inhibits tumor growth by downregulating ACVR2B [39], and it further limits angiogenesis in renal tumors through targeting ECR1 [104]. Additionally, miR-192 suppresses tumor growth in brain cancers, targeting RAB2A in glioblastoma multiforme [23], ZEB2 in glioma [22], and DHFR in medulloblastoma [24]. In retinoblastoma, miR-192 curtails tumor cell migration and invasion by regulating ITGA1 [105].

In ovarian cancer, miR-192 exhibits anti-angiogenic effects by targeting HOXB9 [104]. Bioinformatic studies also identify miR-192-5p as a key miRNA in high-grade primary ovarian tumors [106].

Notably, miR-192 displays a dual role in pancreatic, esophageal, and prostate cancers. In PDAC, miR-192 overexpression promotes tumor growth by repressing SIP1 [70], though other studies suggest it may function as a tumor suppressor by inhibiting EMT via ZEB2 downregulation [69]. In esophageal cancer, miR-192 enhances cisplatin sensitivity by targeting ERCC3/4 [48] and increases tumor cell susceptibility to cytotoxic T lymphocytes by targeting BCL-2 [107]. However, miR-192 promotes proliferation and inhibits apoptosis by suppressing BIM [49], indicating a complex role in esophageal cancer progression and treatment response. In prostate cancer, miR-192 reduces cell proliferation by targeting NOB1 [80], though contrasting findings indicate it may also promote cell cycle progression and proliferation [79].

Mechanism of action of miR-192 as a tumor suppressor

Primarily, miR-192 acts as a tumor suppressor in cancer by regulating specific genes and pathways (Fig. 2). miR-192 is regulated by upstream factors, including non-coding RNAs, pharmaceutical treatments, and other factors.

Fig. 2
figure 2

The Anti-tumor Mechanisms of miR-192 in Cancer. This figure provides a comprehensive summary of the regulatory pathways through which miR-192 exerts tumor-suppressive effects in various cancers, including its upstream regulators, downstream targets, and associated signaling pathways, as well as potential therapeutic implications

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Regulation of miR-192 by upstream factors

Circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) regulate cancer progression by acting as competitive endogenous RNAs (ceRNAs). They sequester miR-192, thereby protecting mRNAs from miRNA-induced degradation [108, 109]. For instance, circKIF5B [86] and circ_0000282 [34] promote osteosarcoma progression by specifically modulating the miR-192/XIAP axis. Similarly, circ_0000189 and circ_0001602 facilitate glioma and AML progression via the miR-192-5p/ZEB2 [22] and miR-192-5p/ZBTB20 axes, respectively [101].The IncRNAs such as SOX2-OT [23], XIST [61], and FTX [30] enhance the production of RAB2A, TRIM25, and EIF5A2 by sponging miR-192, thereby contributing to glioblastoma multiforme, hepatocellular carcinoma, and colorectal cancer progression, respectively.

Several pharmacological agents target miR-192 to regulate cancer progression, offering promising therapeutic strategies. For example, thymoquinone preserves miR-192 levels, inhibiting EMT by increasing E-cadherin expression and inducing apoptosis through the BAX/BCL-2 ratio [64]. BK002, a compound derived from Achyranthes japonica Nakai (AJN) and Melandrium firmum Rohrbach (MFR), both of which have been traditionally used as herbal medicines in China and Korea, induces the expression of miR-192-5p and the C/EBP homologous protein (CHOP). This in turn triggers apoptosis by downregulating BCL-2 and upregulating caspase activity [81]. Simvastatin activates miR-192 to inhibit colon cancer progression by targeting RAB2A [26]. Additionally, curcumin-induced upregulation of miR-192 in NSCLC exhibits anti-proliferative effects by targeting MYC and induces apoptosis by targeting XIAP [75, 84, 110]. Additionally, solamargine that is a natural compound found in Solanum nigrum L., exhibits multifaceted antitumor mechanisms. It elevates miR-192-5p expression through leukemia inhibitory factor (LIF) regulation, effectively inducing autophagy and apoptosis in hepatocellular carcinoma by targeting CYR61 [66]. Matrine, a quinolizidine alkaloid extracted from the traditional Chinese medicinal plant Sophora flavescens, exhibits diverse biological activities, including anticancer, anti-inflammatory, and antiviral effects. In thyroid cancer cells, matrine inhibits migration and invasion by regulating the miR-192-5p/SH3RF3 signaling axis [33].

Other factors also regulate miR-192 expression across various cancers. Nicotine downregulates miR-192 in NSCLC, enhancing proliferation and EMT through RB1 upregulation [85]. Rac GTPase-activating protein 1 (RacGAP1) inhibits miR-192-5p expression by suppressing p53, thereby promoting the carcinogenesis of cervical cancer through RB1 overexpression [93]. The intestinal microflora (MIM) in colon cancer increases miR-192-5p levels, inhibiting progression through BMPR2 suppression [25]. Furthermore, a regulatory feedback loop involving IL-17, miR-192, and IL-17Rs regulates proliferation and EMT in multiple myeloma [98]. tRF-3024b, a specific tRNA-derived fragment, hijacks miR-192-5p in ESCC, enhancing BCL-2 levels and contributing to cytotoxic T lymphocyte resistance [107]. Additionally, a study proposed a model in which p53 typically binds to miR-192, but when p53 binding is lost (due to P53 loss or mutation), Kruppel-like factor 5 (KLF5) binds to miR-192 instead [88]. This interaction leads to the transactivation of miR-192, effectively substituting for p53 function and inhibiting EMT in liver cancer cells. However, the loss of KLF5 results in the inactivation of miR-192 transcription. The expression of ZEB2, a downstream target of miR-192 and a driver of EMT, regulates EMT and invasion in cancers.

Pathways

PI3K/AKT signaling pathway

The PI3K/AKT signaling pathway is a crucial cellular signaling cascade involved in processes such as cell survival, proliferation, growth, and metabolism. Dysregulation of this pathway is associated with the development of several diseases, particularly cancer. Curcumin has shown the ability to inhibit cell proliferation and induce apoptosis in NSCLC cells. These effects are attributed to the upregulation of miR-192-5p, which suppresses the PI3K/AKT signaling pathway [75]. Similarly, BK002 has been shown to hinder the PI3K/AKT signaling pathway by upregulating miR-192, thereby promoting apoptosis in castration-resistant prostate cancer [81]. Furthermore, solamargine has been found to enhance cell apoptosis and autophagy by reducing the phosphorylation of AKT (pAKT) which is a key component of the PI3K/Akt pathway [66].

NF-κB and MAPK signaling pathways

The Nuclear Factor-kappa B (NF-κB) signaling pathway is a pivotal cellular pathway that regulates the transcription of genes involved in immune responses, inflammation, cell survival, and proliferation. In normal cells, NF-κB remains inactive in the cytoplasm by binding to IκB [111]. Upon IκB degradation, NF-κB translocates into the nucleus to activate target genes and execute its biological functions [111]. This pathway is implicated in various pathological processes in cancer. Thymoquinone has been shown to protect liver tissues by preserving miR-192 and interrupting the NF-κB signaling [64]. Additionally, the overexpression of miR-192-5p in TAMs-derived exosomes exhibits a suppressive effect on EMT by inhibiting the NF-κB signaling pathway in esophageal cancer [41].

The Mitogen-Activated Protein Kinase (MAPK) pathway is a fundamental signaling cascade that mediates the transmission of extracellular signals to the nucleus. This pathway regulates a spectrum of cellular processes, including cell growth, proliferation, differentiation, survival, and response to stress. This pathway plays a pivotal role in coordinating cellular responses to various stimuli, including growth factors, cytokines, and environmental stressors. Furthermore, Vacuolar Protein Sorting 33B (VPS33B) has been shown to increase the expression of miR-192-3p through the inactivation of Ras/ERK signaling. This leads to the inhibition of CCNB1 and subsequent blockade of cell proliferation [83].

TGF-β/SMAD and WNT/β-catenin signaling pathways

The Transforming Growth Factor-beta (TGF-β) signaling pathway is a pivotal and multifunctional cascade that intricately regulates diverse cellular processes, including cell proliferation, differentiation, apoptosis, and immune responses. It plays a crucial role in embryonic development, tissue homeostasis, and maintaining immune system balance. Dysregulation of the TGF-β pathway has been linked to various diseases, including cancer and fibrosis. Thymoquinone protects liver tissues by maintaining the levels of miR-192 and E-cadherin while also inhibiting TGF-β signaling [64]. Additionally, ACVR2B, which encodes a protein that functions as a member of the TGF-β signaling pathway, has been identified as a target gene of miR-192 [39]. The downregulating miR-192 may contribute to nephroblastoma development by targeting ACVR2B [39]. These findings emphasize the intricate role of the TGF-β signaling pathway in physiological processes and its involvement in pathological conditions.

The Wnt/β-catenin signaling pathway, also known as the classical Wnt pathway, is a critical and evolutionarily conserved cellular signaling cascade with essential roles in embryonic development, tissue homeostasis, and disease. Dysregulation of this pathway is implicated in multiple cancers. The inhibitory effects of curcumin on NSCLC cells may be associated with the upregulation of miR‑192‑5p. This occurs through the targeting of MYC and the deactivating of Wnt/β-catenin signaling pathway [84]. Delivery of miR-192 via hydrogel-based methods inhibits hepatocellular carcinoma progression by specifically targeting WNT10B, encoding Wnt Family Member 10B protein (WNT10B) which plays a crucial role in the GSK3β/Wnt/β-catenin pathway [112]. This finding highlights the complex role of the Wnt/β-catenin pathway in cellular processes and its potential modulation for therapeutic purposes, particularly involving miRNAs such as miR‑192‑5p.

These intricate regulatory mechanisms underscore the multifaceted role of miR-192 in cancer pathogenesis and underscore its potential as a therapeutic target in diverse malignancies.

Mechanism of action of miR-192 as an oncogene

While miR-192 acts as a tumor suppressor in many cancers, its role as an oncogene has also been observed across different malignancies. The regulation of miR-192 expression and activity in cancer is highly complex, involving multiple factors and signaling pathways (Fig. 3).

Fig. 3
figure 3

The Oncogenic Mechanisms of miR-192 in cancer. This figure presents an overview of the regulatory pathways and molecular interactions through which miR-192 functions as an oncogene in various cancers, highlighting its contribution to tumor progression and malignancy

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Regulation of miR-192 by upstream factors

The combination of bile and acid induces the deregulation of miR-192, a process facilitated by NF-κB activation, is associated with molecular and early histopathological alterations linked to neoplastic transformation [113]. Similarly, the NF-κB inhibitor BAY 11–7072 effectively prevents the acidic bile-induced upregulation of miR-192 in normal human hypopharyngeal cells [114].

Pathways

NF-κB and WNT/β-catenin signaling pathways

miR-192 can activate NF-κB either in various cancers by either directly or indirectly influencing specific target genes. In gastric cancer, miR-192 activates NF-κB by repressing its target RB1, hence promoting tumorigenesis through the induction of EMT [53]. Similarly, miR-192 downregulates the target gene NKRF to directly activate NF-κB, which contributes to tumorigenesis by inhibiting cell apoptosis, enhancing cell cycle progression, and promoting chemo-resistance in lung cancer [77]. Additionally, acidic bile induces upregulation of miR-192 by indirectly activating NF-κB, thereby promoting tumorigenesis in laryngeal cancer [113]. Conversely, the NF-κB pathway inhibitor BAY 11–7072 reduces the expression of miR-192 induced by acidic bile [114].

The WNT signaling pathway is activated by tumor suppressor APC [55] and SMG-1 [115], which have been identified as target genes of miR-192. This activation contributes to the occurrence and development of gastric cancer.

MAPK and PI3K-Akt signaling pathways

miR-192-5p has been shown to promote proliferation and suppress apoptosis in cholangiocarcinoma cells by activating the MEK/ERK pathway [12]. Additionally, miR-192 can activate the PI3K/Akt pathway, contributing to the progression of nasopharyngeal carcinoma [18].

Clinical application of miR-192 in human cancers

In cancer research, miR-192 has emerged as a central focus due to its potential as a diagnostic or prognostic biomarker across various cancer types. Its detectability in various biological fluids and tissues, and resistance to degradation by endogenous ribonuclease, make miR-192 an economical, sensitive, and non-invasive biomarker method. This overview explores the diverse value of miR-192 in cancer diagnosis and prognosis (Table 2).

Table 2 Recent clinical applications of miR-192
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Diagnostic biomarker

Firstly, miR-192 exhibits significant diagnostic potential across multiple cancer types, with its expression in blood (including serum, serum exosomes and PBMCs), tissues, and urinary sediment emerging as a valuable diagnostic marker.

In pancreatic cancer (including PDAC) [68,69,70, 116,117,118] and gastric cancer [43, 57,58,59], miR-192 serves as a reliable biomarker in serum, serum exosomes and tissue samples. Similarly, its presence in serum and tissue from colorectal cancer patients enhances its diagnostic utility [31, 42]. Also, miR-192 levels in hepatocellular carcinoma [119], EOC [52], and HNSCC [17], particularly in serum and serum exosomes, underline its broader clinical applicability. Additionally, circulating miR-192 in serum has shown promise as a marker for the early detection of cholangiocarcinoma [13], multiple myeloma [120] and pediatric AML [44]. Furthermore, mR-192 expression in PBMCs also holds potential for the early diagnosis of CLL [47].

miR-192 expression in tissues has shown diagnostic value in cervical cancer, prostate cancer, and ovarian carcinoma. Notably, miR-192 levels were observed to be six times higher in mucinous tumors compared to other histotypes of ovarian carcinoma [51]. This distinct pattern underlines the potential of miR-192 as a diagnostic biomarker, particularly for mucinous tumors within the spectrum of ovarian carcinoma.

Furthermore, miR-192 levels in urine have emerged as diagnostic biomarkers for bladder cancer [46, 121] and liver fluke-associated cholangiocarcinoma [14]. A decrease of miR-192 expression in the urinary sediment from bladder cancer patients may indicate tumor progression and combining miR-192 expression in urinary sediment with B-ultrasound demonstrates high sensitivity in diagnosing bladder cancer [46].

Prognostic biomarker

Also, miR-192 has demonstrated significant prognostic value across various cancer types, with its expression correlating with disease progression and clinical outcomes. In cholangiocarcinoma, postoperative declines in circulating miR-192 are associated with favorable outcomes, including reduced lymph node metastasis and improved overall survival [13, 15]. Similarly, in NSCLL, miR-192 expression levels in serum and bronchial wash samples are significantly associated with TNM stages, distant metastases, pathological grade, and overall survival, establishing its role as a valuable prognostic marker [73]. In colon cancer, miR-192 levels in serum and tissue samples from colon cancer patients have been linked to poor differentiation, lymphatic metastasis, vascular invasion, and advanced TNM stages, further underscoring the prognostic value of miR-192 [27, 31, 42, 43]. Reduced miR-192 expression in serum from pediatric AML patients has been associated with poor prognosis [44], while miR-192 levels in PBMCs hold potential as a prognostic biomarker for CLL [47]. Exosomal miR-192 also exhibits prognostic significance in hepatocellular carcinoma [119], EOC [52] and gastric cancer [57], where its overexpression correlates with poor overall survival. Likewise, miR-192 expression patterns in colorectal cancer, osteosarcoma, HNSCC, and esophageal cancer tissues correlate with clinical outcomes, offering further prognostic insights [38, 50, 122].

Conclusions

A substantial body of research has explored the context-dependent roles of miR-192 in various cancers, underscoring its promising clinical potential. The distinct expression patterns of miR-192 across cancer types highlight its value as a diagnostic and prognostic biomarker. Notably, aberrant miR-192 levels detected in whole blood, plasma, and other patient specimens suggest its potential utility in non-invasive cancer diagnosis, disease monitoring, and prognostic assessment. Also, miR-192 plays a critical role in the molecular networks underlying tumorigenesis by modulating key functional pathways. These findings highlight miR-192 as potential therapeutic targets, offering new avenues for cancer treatment and intervention. Recent advancements in delivery technologies, including nanoparticles, liposomes, and viral vectors, have improved the feasibility of miRNA-based therapies by enabling precise delivery to tumor sites or systemic administration. Non-invasive delivery strategies are also under development to enhance miRNA transport across cellular barriers, improving targeting specificity and therapeutic efficiency.

This review has comprehensively discussed the aberrant expression, diverse functions, and clinical applications of miR-192 in cancer, with an emphasis on its regulatory mechanisms and networks. However, many of the mechanisms and pathways highlighted are based on preliminary findings, necessitating further validation through larger-scale studies to confirm their clinical relevance and therapeutic applicability.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

miR-192:

microRNA-192

miRNAs:

microRNAs

EMT:

Epithelial-mesenchymal transition

HNSCC:

Hypoxic head and neck squamous cell carcinoma

sEVs:

Small extracellular vesicles

AML:

Acute myeloid leukemia

CLL:

Chronic lymphocytic leukemia

PTC:

Papillary thyroid carcinoma

EOC:

Epithelial ovarian cancer

DOX:

Doxorubicin

TNBC:

Triple-negative breast cancer

PBMCs:

Peripheral blood mononuclear cells

TAMs:

Tumor-associated macrophages

ESCC:

Esophageal squamous cell carcinoma

CSC:

Cancer stem cell

PDAC:

Pancreatic ductal adenocarcinoma

NSCLC:

Non-small-cell lung cancer

MTX:

Methotrexate

circRNAs:

Circular RNAs

lncRNAs:

Long non-coding RNAs

NF-κB:

Nuclear Factor-kappa B

MAPK:

Mitogen-Activated Protein Kinase

TGF-β:

Transforming Growth Factor-beta

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Funding

This work was supported by the Universiti Sains Malaysia, Bridging with Project No: R501-LR-RND003-0000001472-0000.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia

    Yang Yang, Siti Razila Abdul Razak, Ida Shazrina Ismail & Muhammad Amir Yunus

  2. School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China

    Yang Yang & Yanxia Ma

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  1. Yang Yang
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  2. Siti Razila Abdul Razak
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  3. Ida Shazrina Ismail
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  4. Yanxia Ma
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SRAR and ISI contributed to search strategy, design this manuscript sections and prepared tables. YY wrote the original draft and visualized the results. YM designed, structured and edited the manuscript. MAY reviewed and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yanxia Ma or Muhammad Amir Yunus.

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Yang, Y., Razak, S.R.A., Ismail, I.S. et al. Molecular mechanisms of miR-192 in cancer: a biomarker and therapeutic target. Cancer Cell Int 25, 94 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03666-5

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Cancer Cell International

ISSN: 1475-2867

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