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Silencing of ATG4D suppressed proliferation and enhanced cisplatin-induced apoptosis in hepatocellular carcinoma through Akt/Caspase-3 pathway

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Abstract

ATG4D, a member of autophagy-related protein 4 (ATG4) family, plays an interplay role between autophagy and apoptosis in cancers. However, the role of ATG4D in hepatocellular carcinoma (HCC) has not been defined. Herein, this study aimed to investigate the role and the underlying mechanism of ATG4D in regulating HCC cell apoptosis. ATG4D was silenced in MHCC-97L HCC cells, and then cell proliferation and apoptosis were examined. ATG4D expression was significantly upregulated in HCC tissues when compared with paired non-tumor tissues. In vitro assays revealed that silencing of ATG4D significantly suppressed cell proliferation, promoted cell apoptosis, and enhanced sensitivity to cisplatin of MHCC-97L cells. Furthermore, silencing of ATG4D decreased the phosphorylation of Akt and increased the protein level of caspase-3. Taken together, ATG4D may play an oncogenic role in HCC progression. These findings suggest that ATG4D may serve as a therapeutic target for HCC therapy.

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The data could be obtained upon request to the corresponding author.

References

  1. Wallace MC, Preen D, Jeffrey GP, Adams LA (2015) The evolving epidemiology of hepatocellular carcinoma: a global perspective. Exp Rev Gastroenterol Hepatol 9:765–779. https://doi.org/10.1586/17474124.2015.1028363

    Article  CAS  Google Scholar 

  2. Zuo TT, Zheng RS, Zhang SW, Zeng HM, Chen WQ (2015) Incidence and mortality of liver cancer in China in 2011. Chin J Cancer 34:508–513. https://doi.org/10.1186/s40880-015-0056-0

    Article  PubMed  Google Scholar 

  3. Grandhi MS, Kim AK, Ronnekleiv-Kelly SM, Kamel IR, Ghasebeh MA, Pawlik TM (2016) Hepatocellular carcinoma: from diagnosis to treatment. Surg Oncol 25:74–85. https://doi.org/10.1016/j.suronc.2016.03.002

    Article  PubMed  Google Scholar 

  4. Hsieh TC, Wu YC, Sun SS, Yen KY, Kao CH (2016) Treating hepatocellular carcinoma with (90)Y-bearing microspheres: a review. Biomedicine (Taipei) 6:19. https://doi.org/10.7603/s40681-016-0019-z

    Article  Google Scholar 

  5. Yoo BK, Chen D, Su ZZ, Gredler R, Yoo J, Shah K, Fisher PB, Sarkar D (2010) Molecular mechanism of chemoresistance by astrocyte elevated gene-1. Cancer Res 70:3249–3258. https://doi.org/10.1158/0008-5472.can-09-4009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu G, Pei F, Yang F, Li L, Amin AD, Liu S, Buchan JR, Cho WC (2017) Role of autophagy and apoptosis in non-small-cell lung cancer. Int J Mol Sci. https://doi.org/10.3390/ijms18020367

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stordal B, Davey M (2007) Understanding cisplatin resistance using cellular models. IUBMB Life 59:696–699. https://doi.org/10.1080/15216540701636287

    Article  CAS  PubMed  Google Scholar 

  8. Booth LA, Tavallai S, Hamed HA, Cruickshanks N, Dent P (2014) The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal 26:549–555. https://doi.org/10.1016/j.cellsig.2013.11.028

    Article  CAS  PubMed  Google Scholar 

  9. Sheng J, Qin H, Zhang K, Li B, Zhang X (2018) Targeting autophagy in chemotherapy-resistant of hepatocellular carcinoma. Am J Cancer Res 8:354–365

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Levy JMM, Towers CG, Thorburn A (2017) Targeting autophagy in cancer. Nat Rev Cancer 17:528–542. https://doi.org/10.1038/nrc.2017.53

    Article  CAS  PubMed  Google Scholar 

  11. White E, Mehnert JM, Chan CS (2015) Autophagy, metabolism, and cancer. Clin Cancer Res 21:5037–5046. https://doi.org/10.1158/1078-0432.ccr-15-0490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Betin VM, Lane JD (2009) Atg4D at the interface between autophagy and apoptosis. Autophagy 5:1057–1059. https://doi.org/10.4161/auto.5.7.9684

    Article  CAS  PubMed  Google Scholar 

  13. Betin VM, Singleton BK, Parsons SF, Anstee DJ, Lane JD (2013) Autophagy facilitates organelle clearance during differentiation of human erythroblasts: evidence for a role for ATG4 paralogs during autophagosome maturation. Autophagy 9:881–893. https://doi.org/10.4161/auto.24172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu Y, An Y, Wang Y, Zhang C, Zhang H, Huang C, Jiang H, Wang X, Li X (2013) miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol Rep 29:2019–2024. https://doi.org/10.3892/or.2013.2338

    Article  CAS  PubMed  Google Scholar 

  15. Tian J, Tang ZY, Ye SL, Liu YK, Lin ZY, Chen J, Xue Q (1999) New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer 81:814–821. https://doi.org/10.1038/sj.bjc.6690769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lou M, Zhang LN, Ji PG, Feng FQ, Liu JH, Yang C, Li BF, Wang L (2016) Quercetin nanoparticles induced autophagy and apoptosis through AKT/ERK/Caspase-3 signaling pathway in human neuroglioma cells: in vitro and in vivo. Biomed Pharmacother 84:1–9. https://doi.org/10.1016/j.biopha.2016.08.055

    Article  CAS  PubMed  Google Scholar 

  17. Pan W, Li W, Zhao J, Huang Z, Zhao J, Chen S, Wang C, Xue Y, Huang F, Fang Q, Wang J, Brand D, Zheng SG (2019) lncRNA-PDPK2P promotes hepatocellular carcinoma progression through the PDK1/AKT/Caspase 3 pathway. Mol Oncol 13:2246–2258. https://doi.org/10.1002/1878-0261.12553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Song S, Tan J, Miao Y, Li M, Zhang Q (2017) Crosstalk of autophagy and apoptosis: involvement of the dual role of autophagy under ER stress. J Cell Physiol 232:2977–2984. https://doi.org/10.1002/jcp.25785

    Article  CAS  PubMed  Google Scholar 

  19. Gil J, Ramsey D, Pawlowski P, Szmida E, Leszczynski P, Bebenek M, Sasiadek MM (2018) The influence of tumor microenvironment on ATG4D gene expression in colorectal cancer patients. Med Oncol 35:159. https://doi.org/10.1007/s12032-018-1220-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang XM, Li HJ, Wang D, Li C, Chen Q, Li CL (2016) Expressions and clinical significance of autophagy-related genes ATG2B, ATG4D, ATG9B in breast carcinoma. Sichuan Da Xue Xue Bao Yi Xue Ban 47:184–188

    PubMed  Google Scholar 

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Funding

This study was supported by Jiangxi Province Science Foundation for Youths (Award Number 20181BAB215007).

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Author notes

  1. Jing-Yuan Zhao, Xiao-Yun Li and Wen Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Jing-Yuan Zhao, Tian-De Liu, Bo Liang, Yong Huang & Wen Li

  2. Department of Endocrinology, Nanchang Hospital, Sun Yat-Sen University, Nanchang, 330000, China

    Jing-Yuan Zhao

  3. Department of Medical Oncology, The First Affiliated Hospital, He-Nan University, Kaifeng, 475000, China

    Xiao-Yun Li

Authors
  1. Jing-Yuan Zhao
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  2. Xiao-Yun Li
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  3. Tian-De Liu
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  4. Bo Liang
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  5. Yong Huang
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  6. Wen Li
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Contributions

Conceptualization, Methodology: WL, JZ, and XL; Experiments: WL, TL, BL, and YH; Validation: JZ and XL; Writing: WL; Project Administration: JZ and XL All authors reviewed and approved the paper.

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Correspondence to Wen Li.

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The authors declare that they have no competing interests.

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This study was approved by the institutional review board.

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Zhao, JY., Li, XY., Liu, TD. et al. Silencing of ATG4D suppressed proliferation and enhanced cisplatin-induced apoptosis in hepatocellular carcinoma through Akt/Caspase-3 pathway. Mol Cell Biochem 476, 4153–4159 (2021). https://doi.org/10.1007/s11010-021-04224-z

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  • DOI: https://doi.org/10.1007/s11010-021-04224-z

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