Sodium taurocholate co-transporting polypeptide deficiency attenuates hepatocarcinogenesis in mice

Sodium taurocholate co-transporting polypeptide (NTCP) is a liver specific bile acid (BA) transporter; this transporter also serves as a functional receptor for hepatitis B virus (HBV) and hepatitis D virus (HDV). Here, we generated mouse models to investigate the role of NTCP in hepatocarcinogenesis. We report that NTCP-deficient (Slc10a1-/-) mice with long-term hypercholanemia do not develop spontaneous hepatocellular carcinoma (HCC). Using a diethylnitrosamine (DEN)-induced mouse model of HCC, we found that Slc10a1-/- mice exhibited fewer liver tumors, while transgenic mice constitutively overexpressing mouse NTCP in hepatocytes Tg(mNTCP-C9) experienced increased tumor burdens. Intriguingly, the subset of male Slc10a1-/- mice with hypercholanemia exhibited a hepatic female-biased gene expression. Importantly, a majority of the human homologs of genes with significantly hepatic female-biased expression were found to be correlated with improved prognosis in human patients with liver cancer. Our ?ndings indicate that pharmacological manipulation of NTCP function can have a clinical impact on decreasing risk of development or decreasing risk of death liver cancer. Overall design: Methods: Liver mRNA profiles of 8-week old male and female wild-type (WT) and sodium taurocholate cotransporting polypeptide knockout (Slc10a1-/-) mice (2-6 replicates respectively), and 6-month-old male WT and Tg(mNTCP-C9) (5 replicates respectively) were generated respectively by deep sequencing using Illumina Hiseq-2500 platform.