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Int. J. Mol. Sci. 2012, 13(7), 8514-8539; doi:10.3390/ijms13078514
Article

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

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, 1,* , 1
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 and 1
Received: 5 March 2012; in revised form: 26 May 2012 / Accepted: 28 June 2012 / Published: 9 July 2012
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Abstract: 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.
Keywords: hepatocellular carcinoma; hepatitis B virus X protein; miR-338-3p; CyclinD1; cell proliferation hepatocellular carcinoma; hepatitis B virus X protein; miR-338-3p; CyclinD1; cell proliferation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Fu, X.; Tan, D.; Hou, Z.; Hu, Z.; Liu, G. miR-338-3p Is Down-Regulated by Hepatitis B Virus X and Inhibits Cell Proliferation by Targeting the 3′-UTR Region of CyclinD1. Int. J. Mol. Sci. 2012, 13, 8514-8539.

AMA Style

Fu X, Tan D, Hou Z, Hu Z, Liu G. 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. 2012; 13(7):8514-8539.

Chicago/Turabian Style

Fu, Xiaoyu; Tan, Deming; Hou, Zhouhua; Hu, Zhiliang; Liu, Guozhen. 2012. "miR-338-3p Is Down-Regulated by Hepatitis B Virus X and Inhibits Cell Proliferation by Targeting the 3′-UTR Region of CyclinD1." Int. J. Mol. Sci. 13, no. 7: 8514-8539.


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