Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance

Abstract

// Jingting Kang 1 , Jie Wang 1 , Jin Cheng 1 , Zhiliang Cao 2 , Ran Chen 1 , Huiyu Li 2 , Shuang Liu 3 , Xiangmei Chen 1 , Jianhua Sui 2 and Fengmin Lu 1 1 Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, P. R. China 2 National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, 102206, China 3 Beijing Artificial Liver Treatment and Training Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, P.R. China Correspondence to: Fengmin Lu, email: lu.fengmin@hsc.pku.edu.cn Jianhua Sui, email: suijianhua@nibs.ac.cn Keywords: NTCP, hepatocellular carcinoma, survival, cyclin D1, HBV cccDNA Received: March 14, 2016      Accepted: May 29, 2016      Published: June 23, 2016 ABSTRACT The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a liver specific functional receptor for the hepatitis B virus (HBV). Previous studies indicated that the expression of NTCP may be associated with the proliferation status of hepatocytes. However, the involvement of NTCP in hepatocellular carcinoma (HCC) cells proliferation remains unclear. In this study, we confirmed that NTCP was down-regulated in HCC tumor tissues compared with that in the adjacent non-tumor tissues ( P < 0.0001). Clinically, lower expression of NTCP was correlated with poor post-surgery survival rate ( P = 0.0009) and larger tumor tissue mass ( P = 0.003) of HCC patients. This was supported by the finding that ectopic expression of NTCP in both HepG2 and Huh-7 cells could significantly suppress hepatocytes growth by arresting cells in G0/G1 phase. We also discovered that cyclin D1 could transcriptionally suppress NTCP expression by inhibiting the activity of NTCP promoter, while arresting HCC cells in G0/G1 phase by serum starvation could upregulate NTCP mRNA levels. This is the first study to report that the transcriptional inhibition of NTCP expression during cell cycle progression was mediated by cyclin D1. The down-regulated NTCP expression was associated with poor prognosis and lower HBV cccDNA level in HCC patients. Therefore, NTCP expression levels might serve as a novel prognostic predictive marker for post-surgery survival rate of HCC patients.