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Interaction of AURKA with TRIM28 revives dormant LSCC cells via Akt signaling pathway to promote LSCC metastasis

Cancer Cell International volume 25, Article number: 2 (2025) Cite this article

Abstract

Background

Specific molecular mechanisms by which AURKA promoted LSCC metastasis were still unknown.

Methods

Bioinformatic analysis was performed the relationship between TRIM28 and LSCC. Immunohistochemistry, Co-IP assay, Rt-PCR and Western Blot were used to examine the expression of related molecular. Flow cytometry was used to examine cell numbers of G0/G1 phase. Plate colony formation, wound healing, migration, invasion and tail vein injection in nude mice assays were applied to examine the proliferation, movement, migration, invasion and metastasis of LSCC.

Results

TRIM28 was significantly correlated with LSCC. TRIM28 highly expressed in LSCC and the high TRIM28 expression was related to TNM stage and poor clinical prognosis. Furthermore, AURKA could regulate TRIM28. In addition, deprivation TRIM28 expression induced LSCC cells into dormant state and inhibited LSCC metastasis. Akt signaling pathway played an essential role in promoting the tumor-promoting effects induced by TRIM28.

Conclusion

AURKA mediated TRIM28 to revive dormant LSCC cells via Akt signaling pathway to promote LSCC metastasis, targeting TRIM28 might provide a potential treatment strategy for LSCC.

Introduction

Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck [1]. Surgery is currently the main treatment for LSCC, but the 5-year survival rate after standard radical laryngectomy is less than 50%, mainly because tumor is prone to metastasis [2]. At present, LSCC metastasis becomes the main reason for the low survival rate. Therefore, exploring the metastasis mechanism has the important significance for developing an effective clinical prevention program and a new targeted therapy for LSCC.

Ubiquitin ligase is known to be an important component of ubiquitin protease system, which plays an important role in the development of cancer [5]. Ubiquitin-mediated protein ubiquitination plays an important role in maintaining the level of cell cycle regulators, which has attracted the interest of researchers. Ubiquitin ligase TRIM28, a member of TRIM protein family, has been highly concerned as a ubiquitin ligase involved in the development and metastasis of cancer [6]. Bioinformatic analysis showed that TRIM28 was significantly correlated with LSCC, however the definite effect of TRIM28 in the metastasis of LSCC is still unknown.

In our study, we found TRIM28 highly expressed in LSCC tissues and cells and the high TRIM28 expression was related to tumor size, lymphatic metastasis and poor clinical prognosis. Furthermore, the Co-IP assay indicated AURKA could interact with TRIM28. Downregulated AURKA expression, the expression of TRIM28 was reduced, while deprived TRIM28 expression, the expression of AURKA was not altered, which indicated AURKA could regulate TRIM28. In addition, deprivation TRIM28 expression induced LSCC cell into dormant state and inhibited LSCC metastasis. Akt signaling pathway played an essential role in promoting LSCC metastasis and inhibited Akt activity with a specific inhibitor observably impaired the tumor-promoting effects induced by TRIM28. In conclusion, AURKA mediated TRIM28 to revive dormant LSCC cells via Akt signaling pathway to promote LSCC metastasis, targeting AURKA and TRIM28 might provide a potential treatment strategy for LSCC.

Materials and methods

Public database analysis

Public databases including the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA), TIMER, GEPIA, and UALCAN were employed to analyze and visualize the expression and prognosis of AURKA, TRIM28 in HNSCC and LSCC. GEPIA and TIMER were used to analyze the correlation between genes. The analyses of TRIM28-correlated genes were performed by LinkedOmics tool, and further analyses of Gene Ontology (GO) enrichment and protein–protein interaction (PPI) were performed by the Meta-scape analysis tool.

Patient samples and ethical statement

LSCC tumor and non-tumor samples were collected from 30 patients at Shanghai Pudong Gongli Hospital. Human Research Ethics Committee of Hospitals approved our study.

Cell lines

Preserving LSCC cells line (Hep2, TU686, TU212) from the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Culturing cells in DMEM (Gibco company, USA) with 10% FBS with 5% CO2 and 37 °C temperature.

Immunohistochemistry (IHC)

The LSCC was cured by formalin-fixation, paraffin-embedding and dewaxing. Then, the samples were treated with gradient ethanol, and the anti-TRIM28 monoclonal antibody was stained at 4 °C for whole night. Evaluation of specimens through two top pathologists. Judging conflicting specimens by a third pathologist. You usually pick five sights and observe them with a microscope. Positive cells were classified according to the following 4 grades (percent): 0 (< 10%), 1 (10–30%), 2 (30–50%), 3 (> 50%). There were 4 grades (intensity) of staining, 0 (no staining), 1 (weak staining), 2 (medium staining) and 3 (strong staining). Total scores of 1–3 and 4–6 were defined as weak and strong.

Quantitative real-time PCR with RNA extraction (qRT-PCR)

The mRNA level of TRIM28 was quantified using a SYBR Green PCR Core Reagent Kit (Applied Biosystems, Foster City, CA, USA) by QRT-PCR. GAPDH was used as endogenous standard. The data were analyzed by comparison Ct. The specificity of the resultant PCR product was confirmed by melting curves. Primer Express v2.0 (Applied Biosystems, Foster City, CA, USA) was used to design the primers.

Western blot analysis

The protein was extracted with a RIPA buffer (Pierce, Rockford, USA). The BCA Protein Assay Kit was used to measure protein concentration. The collected protein (100 μg/sample) was electrophoresed for 2 h with 10% SDS-PAGE, and 0.22um PVFD membranes (Millipore, MA, USA) was transferred. Then, at 4 °C, the membrane was incubated with a primary antibody (anti-TRIM28, anti-AURKA, anti-p-Akt, anti-Akt and GAPDH, Cell Signaling Technology). The membrane was incubated for 2 h, and the proteins were visualized using a chemiluminescence detection system (Bioscience, Piscataway, NJ, USA).

Co-immunoprecipitation assay

Co-IP assay was performed following the manufacturer’s instructions (Thermo Scientific)4.

Flow cytometry

Flow cytometry Cells were seeded into 6-well plates and washed three times with cold phosphate buffered saline (PBS), and then fixed at 4 °C with 100% ethanol. The cells were then stained at 37 °C with 300 μl PI/Rnase Staining Buffer (BD Pharmingen) for 30 min. Cell cycle phases were analyzed by FACS Calibur (Becton Dickinson, USA). The G0/G1, S or G2/M was quantitated by Modified Software (Becton Dickinson, USA).

Plate colony formation assay

Seeding 1 × 103 and 2 × 103 cells into 6-well plates. Cells were cultivated for 3 weeks in DMEM using 10% FBS, then washed with PBS twice, and then stained for 30 min with crystal violet. Cell colonies were counted in each well.

Wound healing test

Seeding 1 × 106 cells into 6-well plates. The tip of the 20 µl pipette was scratched with the cells to form a straight line overnight. 1X PBS was used for 3 times to remove the floating cells. At last, the wound lines were taken at 0, 24, 48 h (× 2 magnification microscopy).

Migration and invasion assays

Adding the 2 × 105 cells in 200 μl of serum free DMEM onto the top of the transwell chamber (Corning Company, Corning, NY), and the lower level was filled with 600 μl of DMEM containing 10% FBS. The lower filter was stained with crystalline violet solution after one night. Matrigel (Becton Dickinson Labware, Bedford, Massachusetts) was coated on top chamber membrane for invasion assay. Finally, the migration and invasive cells were photographed (× 10 magnification microscopy).

In vivo metastasis

4-week-old male nude mice was raised at Shanghai Jiao Tong University School of Medicine’s Animal Resource Facility. The animal care and experiments were conducted according to “The Care and Use of Experimental Animals” and “The Principles of Treating and Using Vertebrates”, which was approved by Shanghai Jiao Tong University School of Medicine’s Experimental Animal Ethics Committee. The experimental animals were assigned randomly. Cells with the different treatments were injected into nude mice. Mice were taken from Chinese Zoology Research Institute. Four weeks later, the lung metastasis of mice was detected by H&E staining.

Statistical analysis

Statistical analyses were performed using SPSS 13.0 software. The relationship between the TRIM28 expression level was calculated with the Pearson χ2 test. Significant differences between groups were determined using the student t test. Survival data analysis was performed using the Kaplan–Meier and log-rank tests (GraphPad Prism software v6.0).

Results

The expression of AURKA and TRIM28 in pan-cancer

In order to explore the expression of AURKA and TRIM28 in cancer, we analyzed their expression levels by using TIMER database and found that higher expressions of AURKA and TRIM28 in tumor tissue compared to that in normal tissue in HNSCC data set respectively (Fig. 1A and B). We next analyzed the correlations between AURKA expression and TRIM28 expression by using GEPIA. BioGRID and Cytoscape database showed Ten proteins (TRIM28, GMNN, NDN, PML, CHUK, BRCA1, XPO1, CCNE1, TRRAP and NCOR2) are related proteins of AURKA regulating cell cycle transcription factor E2F4 (Fig. 1C).

Fig. 1
figure 1

TRIM28 expression is higher in HNSCC cancer tissue in different cancer types including HNSCC cancer and AURKA positively correlated TRIM28. A, B Differential of AURKA and TRIM28 mRNA expressions between tumor tissue and adjacent normal tissue in TCGA cancer types using TIMER, Gene_DE module. Distributions of gene expression levels are displayed using box plots. C Ten proteins are related proteins of AURKA regulating cell cycle transcription factor E2F4

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TRIM28 was highly expressed in LSCC and correlated to TNM stage

As Fig. 2A and B showed that TRIM28 was highly expressed in LSCC compared to normal tissues in GEO (GSE59102) and TCGA-LSCC data sets. By using GEPIA database, the result was showed that TRIM28 was also highly expressed in HNSCC compared to normal tissues (Fig. 2C). In order to further explore the correlation of TRIM28 and LSCC, the results of UALCAN database indicated that the high expression of TRIM28 was correlated to TNM stage (Fig. 2D and E).

Fig. 2
figure 2

The relationship between the mRNA expression of TRIM28 and the prognosis of patients with LSCC. Kaplan–Meier survival curve comparison of the higher and lower expression of TRIM28. A, B The expression of TRIM28 is significantly higher in LSCC tissue than normal tissue in GEO (GSE59102) and TCGA-LSCC data sets. C GEPIA analysis on differential expression of TRIM28 mRNA between tumor tissue and adjacent normal tissue in HNSCC data set of TCGA. D TRIM28 expression in different N stages. E TRIM28 expression in different tumor grades

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Metabolic process was the most significantly GO biological process enriched with genes related to TRIM28

By using Linked Omics database in HNSCC, we found that 249 genes were positively correlated with TRIM28, 53 genes were negatively correlated TRIM28 (Fig. 3A). Then, we used Metascape to analyze the main enriched Gene Ontology (GO) biological processes of TRIM28 and 302 related genes. They were mainly focused on metabolic process, cellular process, response to stimulus (Fig. 3B). A similar effect was seen in protein–protein interaction (PPI) networks identified by functional cluster analysis (Fig. 3C and D).

Fig. 3
figure 3

GO and PPI analyses of TRIM28-correlated genes. A The genes highly correlated with TRIM28 identified by Pearson correlation analysis in the HNSCC cohort. B Main GO biological processes of all 302 genes correlated with TRIM28. C The PPI networks determined by functional cluster analysis. The different colors represent different functional clusters. D The PPI networks determined by functional cluster analysis. The different colors represent different P values

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TRIM28 is highly expressed in LSCC tissues and cells

In order to explore the role of TRIM28 in promoting the metastasis of LSCC, the expression of TRIM28 was investigated between laryngeal tumor and non-tumor tissues. Results of qRT-PCR were shown that the mRNA level of TRIM28 was observably higher in tumor tissues than non-tumor tissues (**P < 0.01, Fig. 4A, B). Furthermore, 22 of 30 LSCC tissues were categorized as TRIM28 protein strong expression, whereas 8 LSCC tissues and 30 adjacent normal tissues were categorized as TRIM28 protein weak expression. Typical immunostaining of TRIM28 is shown in Fig. 4C. Furthermore, the mRNA and protein levels of TRIM28 were examined in LSCC cells line (Hep2, TU686, TU212 cells). The results shown that the mRNA and protein levels of TRIM28 were higher in TU686 and TU212 cells, whereas lower in Hep2 cells (Fig. 4D–F). All observations indicated that TRIM28 is highly expressed in LSCC tissues and cells.

Fig. 4
figure 4

TRIM28 overexpresses in human LSCC tissues and cells. A, B Expression of TRIM28 mRNA in 30 pairs of LSCC tissues and adjacent non-tumor laryngeal tissues was quantified by qRT-PCR. Data are shown as 2 − ∆Ct (**P < 0.01). C IHC staining of TRIM28 in LSCC tissues (magnification: × 10). D Patients with TRIM28 weak staining had a significantly benign prognosis than those with strong staining, P = 0.0056. E The TRIM28 mRNA expression level in LSCC cell lines was quantified by qRT-PCR. F The TRIM28 protein expression level in LSCC cell lines was examined by Western Blot. G Protein ratio in LSCC cells

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AURKA may regulate TRIM28 in LSCC cells

Considering that TRIM28 was closely related to the occurrence and development of LSCC, the Co-IP assay indicated AURKA could interact with TRIM28 (Fig. 5A, B). And the expression of TRIM28 was reduced when the expression of AURKA was knockdown (Fig. 5C, D), while the expression of AURKA was not altered when the expression of TRIM28 was knockdown (Fig. 5E, F), which indicated AURKA could regulate TRIM28 in LSCC cells.

Fig. 5
figure 5

AURKA regulates TRIM28 in LSCC cells. A, B Co-IP assay showed AURKA interacted with TRIM28. C The expressions of AURKA and TRIM28 were reduced in TU686/si-AURKA and TU212/si-AURKA cells. D Protein ratio in cells. E The expression of TRIM28 was reduced in TU686/si-TRIM28 and TU212/si-TRIM28 cells. F Protein ratio in cells

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TRIM28 promoted dormancy-activated effects induced by AURKA

To further investigate TRIM28 played an important role in reviving dormant LSCC cells, biological cytology experiments were performed. Results showed TU686/si-TRIM28 and TU212/si-TRIM28 cells possess the lower ability of proliferation when compared to control groups (TU686/si-NC and TU212/si-NC cells, *P < 0.05, **P < 0.01, Fig. 6A, B). Moreover, the results of a colony formation assay exhibited the number of colonies of TU686/si-NC (401 ± 55.5) and TU212/si-NC cells (677 ± 110.0) were more than TU686/si-TRIM28 (156 ± 46.5) and TU212/si-TRIM28 cells (285 ± 56.0, *P < 0.05, Fig. 6C, D). And as flow cytometry showed that the percentage of G0/G1 cells was significantly higher in TU686/si-TRIM28 and TU212/si-TRIM28 cells (*P < 0.05, Fig. 6E, F). As Fig. 6G and H showed the dormancy-related proteins were also altered. The expressions of E2F4 and P130 were dramatically increased, and the expression of P107 was observably decreased in TU686/si-nc and TU212/si-nc cells. Finally, Co-IP assay demonstrated the E2F4-P130 complex, unique in quiescent cells, was expressed in TU686/si-TRIM28 cells (Fig. 6I, J). All results suggested that TRIM28 may promote dormancy-activated effects induced by AURKA in LSCC.

Fig. 6
figure 6

TRIM28 promotes dormancy-activated effects induced by AURKA. A, B Knockdown of TRIM28 reduced cell proliferation of TU686 and TU212 cells (*P < 0.05, **P < 0.01). C, D Knockdown of TRIM28 induced the clone formation of TU686 and TU212 cells (*P < 0.05). E, F The percentage of G0/G1 cells was significantly higher in TU686/si-TRIM28 and TU212/si-TRIM28 cells (*P < 0.05). G The dormancy-related proteins were examined by Western Blot. The expressions of E2F4 and P130 were increased, the expressions of E2F4 and P130 were reduced in TU686/si-TRIM28 and TU212/si-TRIM28 cells. H Protein ratio in cells. I, J The complex of E2F4-P130 was detected by Co-IP

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Blocking TRIM28 impaired the metastasis of LSCC in nude mice

Furthermore, cells were inoculated into nude mice by tail vein injection. Four weeks after inoculation, TU686/si-TRIM28 (1.0 ± 1.0), TU212/si-TRIM28 cells (0.7 ± 0.6) with lower TRIM28 expression showed less frequent lung metastases as compared to TU686/si-nc (4 ± 1.5) and TU212/si-nc cells (4 ± 1.7, *P < 0.05, Fig. 7A–D). All above observations indicated that TRIM28 promoted the metastasis of LSCC in nude mice.

Fig. 7
figure 7

TRIM28 induces the metastasis of LSCC in nude mice. A, C TU686/si-TRIM28, TU212/si-TRIM28, TU686/si-nc and TU212/si-nc cells were inoculated into nude mice and pulmonary nodules were observed after 28 days (N = 5/group). H&E stains of pulmonary nodules (100 ×). B, D Pulmonary tissue and nodules were quantified by H&E staining from TU686/si-TRIM28, TU212/si-TRIM28, TU686/si-nc and TU212/si-nc cells (*P < 0.05)

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The dormancy-activated effects induced by AURKA in LSCC are mediated through the activation of Akt signaling pathway

The AKT signaling pathway played a crucial role in the migration and invasion of cancers [7,8,9,10,11]. We suggested that TRIM28 might mediate AKT signaling pathway to promote LSCC metastasis. To better illustrate the important role of AKT in LSCC, Triciribine [12], a AKT inhibitor, was used to treat TU686 and TU212 cells (TU686/Triciribine and TU212/Triciribine cells). As shown in Fig. 5A and B, levels of TRIM28 and p-AKT was lower, level of AKT was not altered in TU686/si-TRIM28 and TU212/si-TRIM28 cells. And level of p-AKT was lower, while levels of TRIM28 and AKT were not changed in TU686/Triciribine and TU212/Triciribine cells, which indicated Akt was the downstream molecules of TRIM28 (Fig. 8C, D).

Fig. 8
figure 8

Akt signaling pathway plays an important role in the dormancy-activated effects induced by AURKA in LSCC. A The expressions of TRIM28 and p-Akt were decreased, the expression of Akt was not altered in TU686/si-TRIM28 and TU212/si-TRIM28 cells. B Protein ratio in cells. C The expression of p-Akt was decreased, the expressions of TRIM28 and Akt were not altered in TU686/Triciribine and TU212/Triciribine cells. D Protein ratio in cells

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Downregulation of Akt expression reduces LSCC cell proliferation, migration, and invasion

Moreover, biological cytology experiments were performed to further identify the role of AKT in the metastasis of LSCC. Results indicated TU686/Triciribine and TU212/Triciribine cells possessed lower cells proliferation when compared to control groups (TU686/parental and TU212/parental cells, *P < 0.05, **P < 0.01, Fig. 9A). In wound-healing assays, TU686/Triciribine and TU212/Triciribine cells were less motile at 48 h compared with TU686/parental and TU212/parental cells (*P < 0.05, Fig. 9B). Moreover, the results of a colony formation assay exhibited the number of colonies of TU686/Triciribine (459 ± 84.5) and TU212/Triciribine cells (453 ± 77.7) were less than TU686/parental (758 ± 111.6) and TU212/parental cells (861 ± 114.3, *P < 0.05, **P < 0.01, Fig. 9C, D). In addition, less TU686/Triciribine (78 ± 11.0) and TU212/Triciribine cells (45 ± 10.5) migrated through transwell chambers compared with TU686/parental (123 ± 8.5) and TU212/parental cells (85 ± 9.3), and TU686/Triciribine (52 ± 4.2) and TU212/Triciribine cells (24 ± 6.7) invaded through matrigel less frequently than TU686/parental (86 ± 7.6) and TU212/parental cells (52 ± 11.8, *P < 0.05, **P < 0.01, Fig. 9E–H). All results suggested that the AKT signaling pathway may promote dormancy-activated effects induced by TRIM28.

Fig. 9
figure 9

Downregulation of Akt expression reduces LSCC cell proliferation, migration, and invasion. A Knockdown of Akt reduced cell proliferation (*P < 0.05, **P < 0.01). B Knockdown of Akt reduced cell movement (*P < 0.05). C, D Knockdown of Akt induced the clone formation of TU686 and TU212 cells (*P < 0.05). E–H Knockdown of Akt induced the ability of migration and invasion of TU686 and TU212 cells (*P < 0.05, **P < 0.01)

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Discussion

LSCC is one of the most common malignant tumors, the metastasis of LSCC is the main reason for the low survival rate and high mortality rate of patients. Accumulating evidence demonstrates that activation of tumor dormancy is one of the mechanisms associated with tumor metastasis [2]. Nevertheless, the concrete molecular mechanisms underlying the activation of quiescence in LSCC remain unknown.

In our previous research, we found that AURKA was highly expressed in human LSCC tissues, and higher expression of AURKA correlated with advanced stage and poorer survival prognosis [3]. AURKA mediated E2F4 to revive dormant LSCC cells to promote LSCC metastasis [4]. The human AURKA gene, located on chromosome 20q13.2, encodes a 46kD serine-threonine kinase consisting of 403 amino acids [13]. AURKA is an important kinase involved in cell division. The expression of AURKA gene is low in G0/G1 phase, but after entering G2 phase, the activity of AURKA mRNA and protein increases rapidly, reaching the peak near G2/M, and remains high in M phase [14, 15]. AURKA is highly expressed in head and neck tumors and correlates with clinical stage, local lymph node metastasis and distant metastasis [16, 17].

It is known that there is an R detection point in the cell cycle between G0/G1, and only cells before the detection point of R can be considered to temporarily leave the cell cycle and enter the G0 stage (dormant stage). The E2F family, cell cycle transcription factors, is an important link in regulating the cell cycle. The E2F transcriptional regulation can be described as the control of cell cycle progression in dormant cells [18]. Currently, the generally recognized G0 indicator is E2F4-P130 complex, and cyclin D is not expressed. At the same time, other auxiliary markers (such as P130, P107, E2F4, Ki67, etc.) can also help judge that tumor cells have entered the dormant stage [19]. Therefore, illustrating specific molecular mechanisms underlying AURKA reviving dormant LSCC to promote LSCC metastasis are of great concern. The key molecules maybe capable to potential prognostic value and potential targets for clinical LSCC treatment.

In our previous research, we found that AURKA was highly expressed in human LSCC tissues, and higher expression of AURKA correlated with advanced stage and poorer survival prognosis for LSCC patients [3]. Furthermore, AURKA mediated E2F4 to revive dormant LSCC cells and then promoted the metastasis of LSCC [4]. Therefore, illustrating specific molecular mechanisms of AURKA mediating E2F4 are of great concern. The key molecules maybe capable to potential prognostic value and potential targets for clinical LSCC treatment.

Here, BioGRID and Cytoscape database were used to identify the proteins associated with AURKA regulation of E2F4. The BioGRID database is a biological universal repository of interactive datasets, an open database dedicated to the management and archiving of protein, gene, and chemical interactions of all major model species and humans. It mainly contains 1598,688 records of biological interactions. 700,000 post-translational modification sites and Chemical-protein interactions of human drug targets. Related proteins of AURKA and E2F4 were searched through BioGRID database, and then Cytoscape was used to merge these related genes. The final bioinformatics analysis showed that: TRIM28, GMNN, NDN, PML, CHUK, BRCA1, XPO1, CCNE1, TRRAP and NCOR2 are related proteins of AURKA regulating cell cycle transcription factor E2F4.

TRIM28 is an oncogene implicated in multiple malignancies. TRIM28 plays an important role in mitotic recombination [20]. Moreover, researchers have reported that f-box protein can act as a specific factor of SKP2 ubiquitin ligase, promoting G1-S transition by targeting the key regulator of protease degradation [21]. ARF Bp1 has the activity of ubiquitin ligase, which restricts the growth rate of tumor cells by ubiquitination of Myc. Knockdown the expression of ARF Bp1 in tumor cell lines U2OS and Hela cells by RNA interference technology can down-regulate the expression of multiple Myc target genes and cause cycle stagnation in G1 phase [22]. Therefore, we hypothesize whether AURKA mediated TRIM28 to active dormant LSCC to promote metastasis.

In our study, TRIM28 was overexpressed in LSCC tissues and cells, and TRIM28 high expression level was observably related to invasion range, lymph node involvement and TNM stage. 60 LSCC patients were followed up by 5 years, patients with high expression of TRIM28 have a high mortality rate which indicated TRIM28 contributes to LSCC metastasis. Ulteriorly, Biological cytology experiments showed TRIM28 may be involved in dormancy-activated effects induced by AURKA.

Multiple different signaling pathways, including MAPK [23], TGF-β [24], Akt [25] and JAK/STAT3 [26], have been reported to regulate dormancy-activated effects. Akt is one of the most important pathways contributing to promote the proliferation of cancers. Here, inhibited Akt activity with a specific inhibitor observably impaired the tumor-promoting effects induced by TRIM28.

In conclusion, AURKA mediated TRIM28 to revive dormant LSCC cells via Akt signaling pathway to promote LSCC metastasis, targeting AURKA and TRIM28 might provide a potential treatment strategy for LSCC.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

Not applicable.

Funding

Funded by Shanghai Healthy Youth Project (Grant No.20234Y0055), Pudong New Area clinical characteristic discipline (PWYts2021-15), Subject Construction Project of Pudong Health Committee of Shanghai (Grant No. PWZy2020-06), Young Medical Talents Training Program of Pudong Health Bureau of Shanghai (Grant No.PWRq2021-06), Gongli Hospital National Fund Cultivation project (Grant No.2022GPY-B04), Shanghai Pudong Science & Technology Development Foundation (No. PKJ2021‐Y13), Key specialty Construction Project of Health Bureau of Shanghai (Grant No. ZX2019C06) and Pudong New Area Clinical Characteristic Discipline (PWYts2021-15).

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Author notes

  1. Liyun Yang and Liang Geng were the first co-author.

Authors and Affiliations

  1. Department of Otolaryngology, Pudong Gongli Hospital, Shanghai, 200135, China

    Liyun Yang, Jing Lu & Shuixian Huang

  2. Department of Otolaryngology, Zhangjiagang Hospital Affiliated to Soochow University, Suzhou, 215600, China

    Liyun Yang, Liang Geng, Xinxin Zhang & Geping Wu

  3. Department of Otolaryngology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Hao Zhang

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  1. Liyun Yang
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  5. Hao Zhang
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  6. Geping Wu
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  7. Shuixian Huang
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Contributions

Performed experiments: YLY, JL, SXH; Data analysis: YLY, ZXX, GL; Manuscript writing: YLY; Revised the manuscript: ZH, WGP; Study design: ZH, WGP; Data interpretation: YLY, WGP.

Corresponding authors

Correspondence to Liyun Yang, Hao Zhang, Geping Wu or Shuixian Huang.

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This study was approved by Institutional Ethnic Committee.

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All patients have provided the Written informed consent for this study.

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The authors declare no competing interests.

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Yang, L., Geng, L., Zhang, X. et al. Interaction of AURKA with TRIM28 revives dormant LSCC cells via Akt signaling pathway to promote LSCC metastasis. Cancer Cell Int 25, 2 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-024-03620-x

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-024-03620-x

Keywords

Cancer Cell International

ISSN: 1475-2867

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