Molecular mechanism of hepatitis B virus (HBV) on suppression of raf kinase inhibitor protein (RKIP) expression

// Xiao-Ke Cheng 1, * , Guo-Zheng Yu 2, * , Xiao-Dong Li 1, 3 , Xue-Qun Ren 1, 4 1 Center for Evidence-Based Medicine, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China 2 Department of General Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi 435000, Hubei Province, China 3 Department of Urology, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China 4 Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, Henan Province, China * Xiao-Ke Cheng and Guo-Zheng Yu are the co-first author Correspondence to: Xue-Qun Ren, email: renxuequn001@163.com Keywords: RKIP, HBV, liver cancer, AP1protein, promoter methylation Received: June 29, 2016     Accepted: November 14, 2016     Published: November 25, 2016 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.