Knockdown of HBV surface antigen gene expression by a lentiviral microRNA-based system inhibits HBV replication and HCC growth

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http://www.ingentaconnect.com/content/bsc/jvh/2011/00000018/00000009/art00008

Journal of Viral Hepatitis, Volume 18, Number 9

Knockdown of HBV surface antigen gene expression by a lentiviral microRNA-based

system inhibits HBV replication and HCC growth

Authors: Xiangji, L.; Feng, X.; Qingbao, C.; Weifeng, T.; Xiaoqing, J.; Baihe,

Z.; Feng, S.; Hongyang, W.; Mengchao, W.

Source: Journal of Viral Hepatitis, Volume 18, Number 9, 1 September 2011 , pp.

653-660(8)

Publisher: Wiley-Blackwell

Abstract:

Summary.  Current options for the treatment of hepatitis B virus (HBV)

infections, a common liver cancer risk factor, are limited. While RNA

interference (RNAi) technologies have been shown to inhibit HBV replication, the

consequent effects on hepatocellular carcinoma (HCC) cell growth are not fully

understood. The aim of this study was to evaluate the effect of RNAi-mediated

decrease in the HBV surface antigen (HBsAg) gene on HBV replication and HCC

growth. A lentiviral microRNA-based system expressing siRNAs targeting the HBsAg

gene (LVshHBS) was developed and transfected into HepG2.2.15 cells (HBV stably

expressing line). We found that LVshHBS significantly inhibited the HBsAg mRNA

and protein levels in the HepG2.2.15 cells, while HBsAg secretion into the

culture supernatant decreased by 70%. BALB/c (nu/nu) mice were injected with

HepG2.2.15 cells transduced with LVshHBS or control vectors to investigate the

effect of inhibiting the HBsAg on the development of tumour growth in a human

HCC nude mice model. Compared with the control, the tumour growth in nude mice

was significantly decreased after injection with LVshHBS. Microarray analysis of

tumour-related genes in LVshHBS-transduced HepG2.2.15 cells showed that the

expressions of genes involved in cell cycle, differentiation and oncogenesis

such as ACP2, BHLHB2, CLK3, CTSC, FOS, NR1D1, PIM1 and SEPT6 genes were

downregulated, while that of the E2F3 gene was upregulated. In conclusion,

lentiviral microRNA-based RNAi against the HBsAg gene not only inhibits HBV

replication but also inhibits the growth of HCC. Downregulation of

growth-related genes is implicated in this mechanism of inhibition.

Document Type: Research article

DOI: 10.1111/j.1365-2893.2010.01346.x

Affiliations:1: Eastern Hepatobiliary Surgery Hospital, Second Military Medical

University, Shanghai, China

Publication date: 2011-09-01