Journal of Hepatocellular Carcinoma (Oct 2020)

miR-3 Encoded by Hepatitis B Virus Downregulates PTEN Protein Expression and Promotes Cell Proliferation

  • Tang J,
  • Xiao XQ,
  • Jiang Y,
  • Tian Y,
  • Peng Z,
  • Yang M,
  • Xu Z,
  • Gong G

Journal volume & issue
Vol. Volume 7
pp. 257 – 269

Abstract

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Jian Tang,1 Xinqiang Xiao,1 Yongfang Jiang,1 Yi Tian,1 Zhongtian Peng,2 Meichan Yang,1 Zhenyu Xu,1 Guozhong Gong1 1The Department of Infectious Disease, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2The Department of Infectious Disease, The First Affiliated Hospital of South China University, Henyang, People’s Republic of ChinaCorrespondence: Guozhong GongThe Department of Infectious Disease, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of ChinaTel +86-731-85292105Fax +86-731-85292173Email [email protected]: Chronic hepatitis B virus (HBV) infection is a key determinant of hepatocellular carcinoma (HCC). However, the mechanism by which HBV contributes to the development of HCC remains to be further explored. HBV-encoded miR-3 (HBV-miR-3) is a newly discovered microRNA that can affect the replication of HBV, but its influence on host genes is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is expressed at low levels in most cancer cells. How HBV-miR-3 acts on PTEN to induce tumorigenesis has not been clarified.Materials and Methods: PTEN protein expression was evaluated in HBV-miR-3-transfected cells and HBV-related liver cancer and paracancerous tissues. A luciferase reporter assay was employed to identify the HBV-miR-3 binding site on the 3ʹ-untranslated region (3ʹ-UTR) of PTEN. Cell apoptosis was assessed by flow cytometry. Cell proliferation was evaluated by colony formation assays. Transwell assays were used to detect cancer cell invasion.Results: HBV-miR-3 was identified only in HBV-replicating HCC cells and HBV-infected patients. HBV-miR-3 expression in liver cancer tissues was higher than that in paracancerous tissues, and the corresponding PTEN expression was significantly decreased. Wild-type HBV-miR-3 bound to the 3ʹ-UTR of PTEN and downregulated its protein expression in a dose-dependent manner. Moreover, the inhibition of HBV-miR-3 rescued PTEN protein expression. Furthermore, HBV-miR-3 reduced liver cancer cell apoptosis, enhanced cell invasion, and promoted cell proliferation.Conclusion: HBV-miR-3 binds to the 3ʹ-UTR of PTEN mRNA and downregulates PTEN protein expression, thereby reducing cell apoptosis and enhancing cell invasion and proliferation. These results indicate that HBV-miR-3 contributes to the development of HBV-related HCC and may be a therapeutic target for this cancer.Keywords: apoptosis, hepatitis B virus, hepatocellular carcinoma, microRNA, PTEN

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