Research On The Role Of MicroRNA-155 In Hepatitis B Or C Related Hepatocellular Carcinomas

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with an estimated 500,000-1,000,000 new cases annually. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection constitute the two most important risk factors for the development of HCC, accounting for over 80%of all HCC globally. Both viruses cause a wide spectrum of clinical manifestations ranging from healthy carrier state to acute and chronic hepatitis, liver cirrhosis, and HCC.MicroRNAs (miRNAs) are noncoding RNAs that have been highly conserved during evolution and have emerged recently as potent regulators of gene expression.11 It is increasingly clear that microRNA-155 (miR-155) plays an important role in the regulation of inflammation, which usually favors the initiation and progression of cancer. MiR-155 has been reported to be substantially upregulated in macrophages activated with poly (I:C). The induction involved TNF-a and c-Jun N-terminal kinase (JNK) pathways, and can be regarded as a common and crucial target of inflammatory mediators. Therefore, miR-155 has the potential to mediate the complex regulation of gene expression associated with an inflammatory response.Recent studies have implicated miRNAs in several cancers, and altered miRNA levels can result in aberrant expression of gene products that might contribute to generating a microenvironment for tumorigenesis, including chronic inflammation and anti-apoptosis. Many studies have reported the levels of miR-155 were significantly increased in tumors, such as Burkitt lymphoma and lung cancer. MiR-155 could provide a potential link between the inflammatory response and cancer because its relation to the development of B-cell malignancies has been documented. However, little is known whether aberrant miR-155 expression during hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is associated with hepatic cell apoptosis and hepatocellular carcinoma (HCC) development.Based on these findings, we tested whether miR-155 contributed to the cancer biology of HBV/HCV-HCC. We characterized the function of miR-155 in vitro with the HCC cell lines and in vivo using athymic nude mice. We evaluated the expression of miRNA in hepatoma cells and HCC tissues by real-time polymerase chain reaction, and defined a target gene and biologically functional effect by flow cytometry and western blot analysis.The levels of miR-155 were increased markedly in macrophages, HepG2.2.15, Huh7 cells transfected with HCV-ORN, and HBV/HCV-HCC patients. Moreover, ectopic expression of miR-155 inhibited apoptosis and promoted proliferation of hepatoma cells, including Huh7 and HepG2, whereas its repression was sufficient to inhibit cell proliferation. Most importantly, Huh7 cells stably transfected with miR-155 contributed to tumor growth in a nude mouse model. Western blot analysis showed that increased levels of miR-155 in HBV/HCV-HCC tissues correlated with decreased Bax expression, a pro-apoptotic gene. miR-155 indirectly inhibited Bax expression by regulating CCAAT/enhancer binding proteinβ(C/EBPβ) activity, rather than p53 or nuclear factor (NF)-κB, although miR-155 could suppress the expression of some important molecules in the NF-κB signaling pathways or p53.These data suggest that miR-155 is a key mediator of inflammation, apoptosis and tumor development, thus offering a new target for prevention of hepatocyte injury and HCC development.