Abstract
Raf kinase inhibitor protein (RKIP) has been shown to be a suppressor of the mitogen-activated protein kinase pathway and is reported to be involved in human malignancy. However, the molecular mechanism of hepatitis B virus (HBV) in regulating RKIP expression is not yet clarified. In this study, we compared RKIP expression in 107 pairs of matched liver cancer and adjacent non-cancerous liver tissues. Among seven HBV-encoded proteins, we found HBV X (HBX) protein could significantly inhibit the expression level of RKIP, indicating that HBV could suppress RKIP expression through regulating HBX. To further elucidate the mechanism, analyses on transcriptional regulation and promoter methylation inhibition were conducted in Huh7 cells. Our results showed that HBX can interact with AP1 protein to inhibit the RKIP transcription. Moreover, we observed that the promoter methylation level of RKIP could be enhanced by HBV. In conclusion, our study revealed that RKIP could act as a molecular marker for HBV-infected liver cancer, but had no tumor-suppressing effect.
Highlights
Hepatitis B virus (HBV) is a section of noncytopathic and double-stranded DNA virus that causes acute and chronic liver diseases
The results showed that Raf kinase inhibitor protein (RKIP) expression was considerably diminished in tumor tissues, suggesting decreased or absence of RKIP expression might contribute to hepatocarcinogenesis
Our results showed that hepatitis B virus (HBV)-1.2 significantly suppressed RKIP luciferase activity by 37% (P
Summary
Hepatitis B virus (HBV) is a section of noncytopathic and double-stranded DNA virus that causes acute and chronic liver diseases. HBV infection is a major public health threat to human health, and there are about one million people dying of liver diseases caused by HBV infection, such as liver failure, cirrhosis, and liver cancer, every year around the world [1]. About 75% of hepatocellular carcinoma (HCC) cases are developed from HBV infection [2]. After Lacent first reported the relationship between HBV and HCC in 1970, a number of other studies further confirmed their conclusion. The mechanism through which HBV infection results in liver cancer remains largely unclear. Studies have demonstrated that hepatitis B virus X (HBX) plays an important role in HBV-mediated HCC. HBX protein is a multifunctional regulatory protein, which can participate in a variety of cellular activities such as intracellular signal transduction, transcription, cell cycle regulation, cell apoptosis and autophagy through interacting with different host cytokines
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