Hyperpolarization-Activated Cyclic Nucleotide-Gated Potassium Channel 3 Promotes HCC Development in a Female-biased Manner

Sex differences in hepatocellular carcinoma (HCC) development are regulated by sex and non-sex chromosomes, sex hormones, and environmental factors. We previously reported that Ncoa5+/- mice develop HCC in a male-biased manner. Here we show that NCOA5 expression was reduced in male patient HCCs while the expression of an NCOA5-interacting tumor suppressor, TIP30, was lower in female HCCs. Tip30 heterozygous deletion did not change HCC incidence in Ncoa5+/- male mice but dramatically increased HCC incidence in Ncoa5+/- female mice, accompanied by hepatic hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) overexpression. HCN3 overexpression cooperated with MYC to promote mouse HCC development, whereas Hcn3 knockout preferentially hindered HCC development in female mice. Furthermore, HCN3 amplification and overexpression occurred in human HCCs and correlated with a poorer prognosis of patients in a female-biased manner. Our results suggest that TIP30 and NCOA5 protect against female liver oncogenesis and that HCN3 is a female-biased HCC driver. Overall design: mRNA profiles of liver from 5-month-old female mice with heterozygous deletion of Ncoa5, Tip30, both Ncoa5 and Tip30, and wild-type female mice. 4 mice in each group.