MicroRNAs-372/373 promote the expression of hepatitis B virus through the targeting of nuclear factor I/B

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http://onlinelibrary.wiley.com/doi/10.1002/hep.24441/abstract

Viral Hepatitis

MicroRNAs-372/373 promote the expression of hepatitis B virus through the

targeting of nuclear factor I/B†

Hongyan Guo1,2,‡, Haiying Liu1,2,‡, Mitchelson1,2,3, Huiying Rao4,

Mingyong Luo2, Lan Xie1,2, Yimin Sun2,3, Liang Zhang2, Ying Lu1,2, Ruyu Liu4,

Aihui Ren2,3, Shuai Liu2,3, Shaozhen Zhou2,3, Jiye Zhu5, Yuxiang Zhou1,2, Ailong

Huang6, Lai Wei4, Yong Guo1,2,*, Jing Cheng1,2,7,*,§

Article first published online: 19 JUL 2011

DOI: 10.1002/hep.24441

Copyright © 2011 American Association for the Study of Liver Diseases

Issue

Hepatology

Volume 54, Issue 3, pages 808–819, 2 September 2011

Abstract

MicroRNAs (miRNAs) play important roles in the posttranscriptional regulation of

gene expression. Recent evidence has indicated the pathological relevance of

miRNA dysregulation in hepatitis virus infection; however, the roles of

microRNAs in the regulation of hepatitis B virus (HBV) expression are still

largely unknown. In this study we identified that miR-373 was up-regulated in

HBV-infected liver tissues and that the members of the miRs-371-372-373

(miRs-371-3) gene cluster were also significantly co-up-regulated in

HBV-producing HepG2.2.15 cells. A positive in vivo association was identified

between hepatic HBV DNA levels and the copy number variation of the miRs-371-3

gene cluster. The enhanced expression of miRs-372/373 stimulated the production

of HBV proteins and HBV core-associated DNA in HepG2 cells transfected with

1.3×HBV. Further, nuclear factor I/B (NFIB) was identified to be a direct

functional target of miRs-372/373 by in silico algorithms and this was

subsequently confirmed by western blotting and luciferase reporter assays.

Knockdown of NFIB by small interfering RNA (siRNA) promoted HBV expression,

whereas rescue of NFIB attenuated the stimulation in the 1.3×HBV-transfected

HepG2 cells. Conclusion: Our study revealed that miRNA (miRs-372/373) can

promote HBV expression through a pathway involving the transcription factor

(NFIB). This novel model provides new insights into the molecular basis in HBV

and host interaction. (HEPATOLOGY 2011;)