miR-338-3p Is Down-Regulated by Hepatitis B Virus X and Inhibits Cell Proliferation by Targeting the 3′-UTR Region of CyclinD1

International Journal of Molecular Sciences

Xiaoyu Fu²  Deming Tan²  Zhouhua Hou²  Zhiliang Hu¹ 

[1] The Second Hospital of Nanjing, Nanjing, Jiangsu, 210000, China; E-Mail:;Department of Infectious Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; E-Mails:

关键词: hepatocellular carcinoma;    hepatitis B virus X protein;    miR-338-3p;    CyclinD1;    cell proliferation;   

DOI  :  10.3390/ijms13078514

来源: mdpi

【 摘 要 】

Hepatitis B virus X protein (HBx) is recognized as an oncogene in hepatocellular carcinoma (HCC). HBx regulates microRNA expression, including down-regulating miR-338-3p in LO2 cells. Here, we investigated miR-338-3p function in HBx-mediated hepatocarcinogenesis. In 23 HBV-infected HCC clinical patient tumor and adjacent non-tumor control tissues, 17 and 19 tumors expressed HBx mRNA and protein, respectively. When considered as a group, HBV-infected HCC tumors had lower miR-338-3p expression than controls; however, miR-338-3p was only significantly down-regulated in HBx-positive tumors, indicating that HBx inversely correlated with miR-338-3p. Functional characterization of miR-338-3p indicated that miR-338-3p mimics inhibited cell proliferation by inducing cell cycle arrest at the G1/S phase as assessed by EdU and cell cycle assays in HBx-expressing LO2 cells. CyclinD1, containing two putative miR-338-3p targets, was confirmed as a direct target using 3′-UTR luciferase reporter assays from cells transfected with mutated binding sites. Mutating the 2397–2403 nt binding site conferred the greatest resistance to miR-338-3p suppression of CyclinD1, indicating that miR-338-3p suppresses CyclinD1 at this site. Overall, this study demonstrates that miR-338-3p inhibits proliferation by regulating CyclinD1, and HBx down-regulates miR-338-3p in HCC. This newly identified miR-338-3p/CyclinD1 interaction provides novel insights into HBx-mediated hepatocarcinogenesis and may facilitate therapeutic development against HCC.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.