Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway----中国科学院微生物研究所

科研成果

论文题目:	Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway
作者:	Liu Ningning Jiao Tong, Huang Yan, Liu Wenjun, Li Zhiwei, Ye Xin.
联系作者:
刊物名称:	J Virol
期:	89
卷:	5
页:	2739-49
年份:	2015
影响因子:	4.609
论文下载:	http://jvi.asm.org/content/89/5/2739.long
摘要:	Hepatitis B virus (HBV) infection causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). Previously, we found that HBV mRNAs can absorb microRNA-15a (miR-15a) to affect apoptosis through the Bcl-2 pathway. We asked whether HBV could inhibit apoptosis and promote tumorigenesis through different pathways. In this study, we found that the transforming growth factor beta (TGF-beta) pathway-inhibitory factor Smad7 is a novel target of miR-15a. We demonstrated that HBV can upregulate the level of Smad7 by downregulating miR-15a. Furthermore, we examined the level of Smad7 in liver samples from HBV-infected HCC patients and found that HBV mRNAs are positively correlated with the level of Smad7. By taking the approach of using immunoblotting and luciferase reporter assays, we revealed that HBV can abrogate TGF-beta signaling via upregulating Smad7. By using annexin V staining and caspase 3/7 activity assays, we found that HBV can inhibit TGF-beta-induced apoptosis of HepG2 cells. We also showed that HBV can promote tumor growth in BALB/c nude mice through upregulating the expression of Smad7. In conclusion, we demonstrated that HBV can upregulate Smad7 expression and inhibit TGF-beta signaling, which makes the cells resistant to TGF-beta-induced apoptosis and promotes tumorigenesis. IMPORTANCE: Hepatitis B virus (HBV) infection causes chronic hepatitis, which can eventually lead to hepatocellular carcinoma (HCC). TGF-beta signaling is closely linked to liver fibrosis, cirrhosis, and subsequent HCC progression and plays a unique role in the pathogenesis of HCC. At the early stage of tumor formation, TGF-beta functions as a tumor suppressor that inhibits cell proliferation and induces apoptosis. Previously, we found that HBV mRNAs can sponge off miR-15a to affect apoptosis through the Bcl-2 pathway. In this study, we identified that the TGF-beta-inhibitory factor Smad7 is a novel target of miR-15a. We reveal that HBV can abrogate TGF-beta signaling via upregulating Smad7, inhibit TGF-beta-induced apoptosis, as well as promote tumor development. Our study provides evidence to support the idea that viral RNAs can exert their functions as competing endogenous RNAs (ceRNAs) toward microRNA and participate in important cellular processes.