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Upregulation of Excision Repair Cross-Complementation Group 6-Like (ERCC6L) Promotes Tumor Growth in Hepatocellular Carcinoma

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Abstract

Background

Excision repair cross-complementation group 6-like (ERCC6L) is overexpressed in some malignancies; however, its role in hepatocellular carcinoma (HCC) remains to be further investigated.

Aims

In the present study, we explored the expression and function of ERCC6L in HCC.

Methods and Results

We investigated the expression of ERCC6L by microarray analysis, using the Cancer Genome Atlas database, and by HCC tissue microarray. The results showed that ERCC6L expression was upregulated in tumor specimens and HCC cell lines. High ERCC6L expression in tumor tissues was significantly correlated with poor prognosis and could serve as an independent prognostic indicator for HCC patients. Results of in vitro and in vivo assays revealed that ERCC6L substantially promoted cell proliferation, and our flow cytometry analysis revealed that this was accomplished by acceleration of the G1/S transition. Finally, gene set enrichment analysis and western blotting results indicated that ERCC6L might regulate HCC proliferation by activating p53 signaling.

Conclusions

Our study suggests that ERCC6L plays an important role in HCC proliferation and that it might serve as a promising therapeutic target in HCC.

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References

  1. 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. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  2. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet (London, England). 2018;391:1301–1314. https://doi.org/10.1016/s0140-6736(18)30010-2.

    Article  Google Scholar 

  3. Yu XN, Chen H, Liu TT, Wu J, Zhu JM, Shen XZ. Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway? Biochim Biophys Acta. 2019;1871:379–391. https://doi.org/10.1016/j.bbcan.2019.03.001.

    Article  CAS  Google Scholar 

  4. Xu Y, Chen X, Li Y. Ercc6l, a gene of SNF2 family, may play a role in the teratogenic action of alcohol. Toxicol Lett. 2005;157:233–239. https://doi.org/10.1016/j.toxlet.2005.02.013.

    Article  CAS  PubMed  Google Scholar 

  5. Albers E, Sbroggio M, Pladevall-Morera D, et al. Loss of PICH results in chromosomal instability, p53 activation, and embryonic lethality. Cell Rep. 2018;24:3274–3284. https://doi.org/10.1016/j.celrep.2018.08.071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baumann C, Korner R, Hofmann K, Nigg EA. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell. 2007;128:101–114. https://doi.org/10.1016/j.cell.2006.11.041.

    Article  CAS  PubMed  Google Scholar 

  7. Holtrich U, Wolf G, Brauninger A, et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci USA. 1994;91:1736–1740. https://doi.org/10.1073/pnas.91.5.1736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Knecht R, Elez R, Oechler M, Solbach C, von Ilberg C, Strebhardt K. Prognostic significance of polo-like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Can Res. 1999;59:2794–2797.

    CAS  Google Scholar 

  9. Takai N, Hamanaka R, Yoshimatsu J, Miyakawa I. Polo-like kinases (Plks) and cancer. Oncogene. 2005;24:287–291. https://doi.org/10.1038/sj.onc.1208272.

    Article  CAS  PubMed  Google Scholar 

  10. Wolf G, Elez R, Doermer A, et al. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene. 1997;14:543–549. https://doi.org/10.1038/sj.onc.1200862.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang G, Yu Z, Fu S, et al. ERCC6L that is up-regulated in high grade of renal cell carcinoma enhances cell viability in vitro and promotes tumor growth in vivo potentially through modulating MAPK signalling pathway. Cancer Gene Ther. 2019;26:323–333. https://doi.org/10.1038/s41417-018-0064-8.

    Article  CAS  PubMed  Google Scholar 

  12. Huang Y, Li W, Yan W, et al. Loss of PICH promotes chromosome instability and cell death in triple-negative breast cancer. Cell Death Dis. 2019;10:428. https://doi.org/10.1038/s41419-019-1662-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu J, Sun J, Zhang Q, Zeng Z. shRNA knockdown of DNA helicase ERCC6L expression inhibits human breast cancer growth. Mol Med Rep. 2018;18:3490–3496. https://doi.org/10.3892/mmr.2018.9317.

    Article  CAS  PubMed  Google Scholar 

  14. Pu SY, Yu Q, Wu H, et al. ERCC6L, a DNA helicase, is involved in cell proliferation and associated with survival and progress in breast and kidney cancers. Oncotarget. 2017;8:42116–42124. https://doi.org/10.18632/oncotarget.14998.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ma XL, Jiang M, Zhao Y, et al. Application of serum annexin A3 in diagnosis, outcome prediction and therapeutic response evaluation for patients with hepatocellular carcinoma. Ann Surg Oncol. 2018;25:1686–1694. https://doi.org/10.1245/s10434-018-6402-0.

    Article  PubMed  Google Scholar 

  16. Yang XR, Xu Y, Yu B, et al. CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:5518–5527. https://doi.org/10.1158/1078-0432.ccr-09-0151.

    Article  CAS  Google Scholar 

  17. Jiang XM, Yu XN, Huang RZ, et al. Prognostic significance of eukaryotic initiation factor 4E in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2016;142:2309–2317. https://doi.org/10.1007/s00432-016-2232-2.

    Article  CAS  PubMed  Google Scholar 

  18. Sun J, Zhou C, Ma Q, et al. High GCLC level in tumor tissues is associated with poor prognosis of hepatocellular carcinoma after curative resection. J Cancer. 2019;10:3333–3343. https://doi.org/10.7150/jca.29769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu Z, Sun Q, Wang X. PLK1, a potential target for cancer therapy. Transl Oncol. 2017;10:22–32. https://doi.org/10.1016/j.tranon.2016.10.003.

    Article  PubMed  Google Scholar 

  20. Ran Z, Chen W, Shang J, et al. Clinicopathological and prognostic implications of polo-like kinase 1 expression in colorectal cancer: a systematic review and meta-analysis. Gene. 2019;721:144097. https://doi.org/10.1016/j.gene.2019.144097.

    Article  CAS  PubMed  Google Scholar 

  21. Affatato R, Carrassa L, Chila R, Lupi M, Restelli V, Damia G. Identification of PLK1 as a new therapeutic target in mucinous ovarian carcinoma. Cancers. 2020;. https://doi.org/10.3390/cancers12030672.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bhola NE, Jansen VM, Bafna S, et al. Kinome-wide functional screen identifies role of PLK1 in hormone-independent. ER-positive breast cancer. Cancer Res. 2015;75:405–414. https://doi.org/10.1158/0008-5472.can-14-2475.

    Article  CAS  PubMed  Google Scholar 

  23. Helmke C, Becker S, Strebhardt K. The role of Plk3 in oncogenesis. Oncogene. 2016;35:135–147. https://doi.org/10.1038/onc.2015.105.

    Article  CAS  PubMed  Google Scholar 

  24. Massague J. G1 cell-cycle control and cancer. Nature. 2004;432:298–306. https://doi.org/10.1038/nature03094.

    Article  CAS  PubMed  Google Scholar 

  25. Mladenov E, Magin S, Soni A, Iliakis G. DNA double-strand-break repair in higher eukaryotes and its role in genomic instability and cancer: cell cycle and proliferation-dependent regulation. Semin Cancer Biol. 2016;37–38:51–64. https://doi.org/10.1016/j.semcancer.2016.03.003.

    Article  CAS  PubMed  Google Scholar 

  26. Tsai CH, Chen YJ, Yu CJ, et al. SMYD3-mediated H2A.Z.1 methylation promotes cell cycle and cancer proliferation. Can Res. 2016;76:6043–6053. https://doi.org/10.1158/0008-5472.can-16-0500.

    Article  CAS  Google Scholar 

  27. Maddika S, Ande SR, Panigrahi S, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updates Rev Comment Antimicrob Anticancer Chemother. 2007;10:13–29. https://doi.org/10.1016/j.drup.2007.01.003.

    Article  CAS  Google Scholar 

  28. Murray JM, Carr AM. Integrating DNA damage repair with the cell cycle. Curr Opin Cell Biol. 2018;52:120–125. https://doi.org/10.1016/j.ceb.2018.03.006.

    Article  CAS  PubMed  Google Scholar 

  29. Ke Y, Huh JW, Warrington R, et al. PICH and BLM limit histone association with anaphase centromeric DNA threads and promote their resolution. EMBO J. 2011;30:3309–3321. https://doi.org/10.1038/emboj.2011.226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kmet LM, Cook LS, Magliocco AM. A review of p53 expression and mutation in human benign, low malignant potential, and invasive epithelial ovarian tumors. Cancer. 2003;97:389–404. https://doi.org/10.1002/cncr.11064.

    Article  CAS  PubMed  Google Scholar 

  31. Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23:7518–7528. https://doi.org/10.1200/jco.2005.00.471.

    Article  CAS  Google Scholar 

  32. Gao Q, Zhu H, Dong L, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell. 2019;179:561.e22–577.e22. https://doi.org/10.1016/j.cell.2019.08.052.

    Article  CAS  Google Scholar 

  33. Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–414. https://doi.org/10.1038/nrc2657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Georgakilas AG, Martin OA, Bonner WM. p21: a two-faced genome guardian. Trends Mol Med. 2017;23:310–319. https://doi.org/10.1016/j.molmed.2017.02.001.

    Article  CAS  PubMed  Google Scholar 

  35. Johnson LN, De Moliner E, Brown NR, et al. Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2. Pharmacol Ther. 2002;93:113–124. https://doi.org/10.1016/s0163-7258(02)00181-x.

    Article  CAS  PubMed  Google Scholar 

  36. Wadler S. Perspectives for cancer therapies with cdk2 inhibitors. Drug Resist Updates Rev Comment Antimicrob Anticancer Chemother. 2001;4:347–367. https://doi.org/10.1054/drup.2001.0224.

    Article  CAS  Google Scholar 

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Acknowledgments

This study was funded by the National Natural Science Foundation of China (Grant Numbers 81760497 and 81960446).

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Authors and Affiliations

  1. Department of Gastroenterology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, 570100, China

    Guangcong Zhang, Jiamei Ma, Xiaoxi Huang & Xuemei Jiang

  2. Department of Hepatobiliary Surgery, Hainan General Hospital, Haikou, 570100, China

    Ju Xiong

  3. Department of Gastroenterology, Hainan General Hospital, Haikou, 570100, China

    Xiangyang Han & Xuemei Jiang

  4. Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200030, China

    Xiangnan Yu

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  1. Guangcong Zhang
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Correspondence to Xuemei Jiang.

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Zhang, G., Ma, J., Xiong, J. et al. Upregulation of Excision Repair Cross-Complementation Group 6-Like (ERCC6L) Promotes Tumor Growth in Hepatocellular Carcinoma. Dig Dis Sci 66, 1097–1109 (2021). https://doi.org/10.1007/s10620-020-06277-4

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