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Knockdown of TRIM15 inhibits the proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inactivation of the Wnt/β-catenin signaling pathway

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Abstract

TRIM15 is a member of tripartite motif-containing protein (TRIM) protein family, which plays important roles in several cancers. The aim of the present study was to evaluate the role of TRIM15 in esophageal squamous cell carcinoma (ESCC). Our results showed that TRIM15 was upregulated in human ESCC tissues and cell lines. In vitro studies showed that knockdown of TRIM15 significantly inhibited the proliferation, migration, and invasion of ESCC cells. Knockdown of TRIM15 caused a significant increase in E-cadherin expression, as well as decreases in expression of N-cadherin and Vimentin proteins. Moreover, in vivo assay proved that tumor growth was suppressed by knockdown of TRIM15. Furthermore, the protein expression levels of β-catenin, C-myc, and CyclinD1 were markedly decreased in sh-TRIM15-infected ESCC cells. Additionally, treatment with LiCl reversed the inhibitory effects of TRIM15 knockdown on ESCC cells. In conclusion, these findings indicated that knockdown of TRIM15 blocked the growth and metastasis of ESCC in part through inhibiting the Wnt/β-catenin signaling pathway. Thus, TRIM15 might serve as a promising therapeutic target for ESCC.

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References

  • Abnet CC, Arnold M, Wei WQ (2018) Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 154(2):360–373

    Article  Google Scholar 

  • Chen W, Lu C, Hong J (2018) TRIM15 exerts anti-tumor effects through suppressing cancer cell invasion in gastric adenocarcinoma. Med Sci Monit 24:8033–8041

    Article  CAS  Google Scholar 

  • Chi J, Yang Q, Xie XF, Yang XZ, Zhang MY, Wang HY, Xu GL (2016) Clinical significance and prognostic value of TRIM24 expression in esophageal squamous cell carcinoma. Aging 8(9):2204–2221

    Article  CAS  Google Scholar 

  • Deng F, Zhou K, Cui W, Liu D, Ma Y (2015) Clinicopathological significance of wnt/beta-catenin signaling pathway in esophageal squamous cell carcinoma. Int J Clin Exp Pathol 8(3):3045–3053

    PubMed  PubMed Central  Google Scholar 

  • Esposito D, Koliopoulos MG, Rittinger K (2017) Structural determinants of TRIM protein function. Biochem Soc Trans 45(1):183–191

    Article  CAS  Google Scholar 

  • Han X, Huang C, Qu X, Liu S, Yang X, Wang Y, Bie F, Liu Q, Du J (2019) Tripartite motif-containing 15 overexpression in non-small cell lung cancer is associated with poor patient prognoses. J Cancer 10(4):843–852

    Article  CAS  Google Scholar 

  • Hatakeyama S (2017) TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci 42(4):297–311

    Article  CAS  Google Scholar 

  • Hirano H, Kato K (2019) Systemic treatment of advanced esophageal squamous cell carcinoma: chemotherapy, molecular-targeting therapy and immunotherapy. Jpn J Clin Oncol 49(5):412–420

    Article  Google Scholar 

  • Huang FL, Yu SJ (2018) Esophageal cancer: Risk factors, genetic association, and treatment. Asian J Surg 41(3):210–215

    Article  Google Scholar 

  • Kimura T, Jain A, Choi SW, Mandell MA, Schroder K, Johansen T, Deretic V (2015) TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol 210(6):973–989

    Article  CAS  Google Scholar 

  • Krishnamurthy N, Kurzrock R (2018) Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev 62:50–60

    Article  CAS  Google Scholar 

  • Kwon YT, Ciechanover A (2017) The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem Sci 42(11):873–886

    Article  CAS  Google Scholar 

  • Lee HJ (2018) The role of tripartite motif family proteins in TGF-beta signaling pathway and cancer. J Cancer Prev 23(4):162–169

    Article  Google Scholar 

  • Lee OH, Lee J, Lee KH, Woo YM, Kang JH, Yoon HG, Bae SK, Songyang Z, Oh SH, Choi Y (2015) Role of the focal adhesion protein TRIM15 in colon cancer development. Biochim Biophys Acta 1853(2):409–421

    Article  CAS  Google Scholar 

  • Li J, Ying J, Fan Y, Wu L, Ying Y, Chan AT, Srivastava G, Tao Q (2010) WNT5A antagonizes WNT/beta-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma. Cancer Biol Ther 10(6):617–624

    Article  CAS  Google Scholar 

  • Li F, Zhang L, Li W, Deng J, Zheng J, An M, Lu J, Zhou Y (2015) Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget 6(8):6001–6013

    Article  Google Scholar 

  • Lin J (2017) Esophageal squamous cell carcinoma and adenocarcinoma: At the Gates of Mordor. J Thorac Cardiovasc Surg 154(4):1444–1445

    Article  Google Scholar 

  • Liu B, Li X, Liu F, Li F, Wei S, Liu J, Lv Y (2019) Expression and significance of TRIM 28 in squamous carcinoma of esophagus. Pathol Oncol Res 25(4):1645–1652

    Article  CAS  Google Scholar 

  • Ma S, Paiboonrungruan C, Yan T, Williams KP, Major MB, Chen XL (2018) Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target. Ann N Y Acad Sci 1434(1):164–172

    Article  CAS  Google Scholar 

  • Ma L, Yao N, Chen P, Zhuang Z (2019) TRIM27 promotes the development of esophagus cancer via regulating PTEN/AKT signaling pathway. Cancer Cell Int 19:283

    Article  Google Scholar 

  • Marin I (2012) Origin and diversification of TRIM ubiquitin ligases. PLoS One 7(11):e50030

    Article  CAS  Google Scholar 

  • Ozato K, Shin DM, Chang TH, Morse HC III (2008) TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol 8(11):849–860

    Article  CAS  Google Scholar 

  • Varshavsky A (2017) The ubiquitin system, autophagy, and regulated protein degradation. Annu Rev Biochem 86:123–128

    Article  CAS  Google Scholar 

  • Venuto S, Merla G (2019) E3 ubiquitin ligase TRIM proteins, cell cycle and mitosis. Cells 8(5):510

    Article  CAS  Google Scholar 

  • Vilchez V, Turcios L, Marti F, Gedaly R (2016) Targeting Wnt/beta-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol 22(2):823–832

    Article  CAS  Google Scholar 

  • Watanabe M, Hatakeyama S (2017) TRIM proteins and diseases. J Biochem 161(2):135–144

    CAS  PubMed  Google Scholar 

  • Yao H, Ashihara E, Maekawa T (2011) Targeting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin Ther Target 15(7):873–887

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by a standardized endoscopic diagnosis and treatment of early upper gastrointestinal cancer and related proteins (No.2018ZDXM-SF-055).

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Author notes

  1. Li Zhang and Bin Qin contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, No.157, Xiwu Road, Xincheng District, Xi’an, 710004, Shaanxi Province, China

    Li Zhang, Bin Qin, Baicang Zou, Shenhao Wang, Xiaojing Quan, Jinhai Wang & Hongli Zhao

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  1. Li Zhang
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  2. Bin Qin
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  3. Baicang Zou
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  4. Shenhao Wang
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  6. Jinhai Wang
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  7. Hongli Zhao
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Contributions

Baicang Zou designed this manuscript. Li Zhang wrote this manuscript. Bin Qin, Shenhao Wang and Xiaojing Quan performed experiments. Jinhai Wang analyzed the data. Hongli Zhao revised the language of the manuscript; all the authors approved the manuscript for submission.

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Correspondence to Baicang Zou.

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Supplementary Information

Supplementary Fig. 1.

Immunohistochemistry staining of TRIM15 in human ESCC tissues and in adjacent non-tumor tissues. (PNG 40 kb)

High Resolution Image (TIF 585 kb)

Supplementary Fig. 2.

Sh2-TRIM15 inhibits the proliferation of ESCC cells. EC-1 and KYSE-410 cells were infected with sh2-TRIM15 or sh-scramble. After 48 h post infection, the efficiency of TRIM15 knockdown was assessed by western blotting. (A-B) The protein expression levels of TRIM15 were decreased after infection with LV-sh2-TRIM15. (C-D) Cell proliferation of EC-1 and KYSE-410 cells was evaluated using CCK-8 assay. n = 6. *p < 0.05 vs. sh-scramble group. (PNG 772 kb)

Supplementary Fig. 3.

Sh2-TRIM15 suppresses the migration and invasion of ESCC cells. After 48 h post infection, transwell assay was used to assess cell migration and invasion. (A-B) Cell migration of EC-1 and KYSE-410 cells was measured. (C-D) Cell invasion of EC-1 and KYSE-410 cells was detected. n = 5. *p < 0.05 vs. sh-scramble group. (PNG 42 kb)

High Resolution Image (TIF 2050 kb)

Supplementary Fig. 4.

Sh2-TRIM15 inhibits the EMT process in ESCC cells. The expression levels of three important EMT correlative markers including E-cadherin, N-cadherin and Vimentin in both TRIM15-silencing EC-1 (A) and KYSE-410 cells (B) were measured by using western blotting. n = 4. *p < 0.05 vs. sh-scramble group. (PNG 835 kb)

Supplementary Fig. 5.

Sh2-TRIM15 inhibits the Wnt/β-catenin pathway in ESCC cells. (A) The expression levels of β-catenin, C-myc, and CyclinD1 were measured by western blotting in TRIM15-silencinged EC-1 cells. (B-D) Quantification analysis of β-catenin, C-myc, and CyclinD1. n = 5. *p < 0.05 vs. sh-scramble group. (PNG 674 kb)

Supplementary Fig. 6.

The effects of TRIM15 overexpression on cell proliferation, migration and invasion in HET-1A esophageal epithelial cells. HET-1A cells were transfected with pcDNA3.1-TRIM15 or pcDNA3.1. (A) Cell proliferation was evaluated using CCK-8 assay. (B and C) Transwell assay was used to assess cell migration and invasion. *p < 0.05 vs. pcDNA3.1 group. (PNG 34 kb)

High Resolution Image (TIF 1775 kb)

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Zhang, L., Qin, B., Zou, B. et al. Knockdown of TRIM15 inhibits the proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inactivation of the Wnt/β-catenin signaling pathway. J Bioenerg Biomembr 53, 213–222 (2021). https://doi.org/10.1007/s10863-021-09872-w

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