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.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancerrelated deaths worldwide [1]
NTCP expression level is significantly higher in the hepatitis B virus (HBV) closed circular DNA (cccDNA) positive tumor tissues Since NTCP has been shown to be a functional cellular receptor responsible for HBV entry into hepatocytes [9], we investigated whether the lower/ undetectable NTCP expression in tumor tissues could affect the HBV cccDNA reservoirs in hepatocellular carcinoma (HCC)
Consistent with this report, our study demonstrated that the NTCP expression level in HCC tumor tissues was significantly lower than that in the adjacent non-tumor tissues
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancerrelated deaths worldwide [1]. Epidemiological evidence has clearly shown that chronic hepatitis B virus (HBV) infection is the major risk factor for the development of HCC [2]. It is known that chronic HBV infection and persistent inflammation may result in liver regeneration and cirrhosis, thereby inducing malignant transformation of liver cells [3, 4]. The Na+/taurocholate cotransporter polypeptide (NTCP, SLC10A1) is the main hepatocellular sodiumdependent uptake system for conjugated bile acids in human and rodent livers [7, 8]. It was originally discovered and cloned by researchers based on its ability to bind to and transfer bile acids from the blood to liver parenchymal cells. This work revealed an association between NTCP transcription regulation and the proliferation status of hepatocytes, suggesting a mechanism whereby quiescent hepatocytes switching to rapid cell proliferation could silence NTCP expression
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