男性肝细胞癌（HCC）发展的性别差异由性和非性染色体、性激素和环境因素共同调节。我们先前报道了Ncoa5+/-小鼠以男性为主发展HCC的现象。在这里，我们展示了NCOA5在男性患者HCC中表达下调，而与NCOA5相互作用的肿瘤抑制因子TIP30在女性HCC中表达较低的情况。TIP30杂合缺失不会改变Ncoa5+/-雄性小鼠的HCC发生率，但会显著增加Ncoa5+/-雌性小鼠的HCC发生率，并伴随着肝脏高极化活化环核苷酸门控离子通道3（HCN3）的过度表达。HCN3的过度表达与MYC合作促进了小鼠HCC的发展，而Hcn3基因敲除在雌性小鼠中优先阻碍HCC的发展。此外，HCN3基因扩增和过度表达在人类HCC中普遍存在，并与女性HCC患者预后较差相关。我们的结果表明，TIP30和NCOA5对女性肝癌发生具有保护作用，而HCN3是一种有女性偏倚的HCC促进因子。版权所有 © 2023 作者。Elsevier Inc. 版权所有。

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 is reduced in male patient HCCs while the expression of an NCOA5-interacting tumor suppressor, TIP30, is lower in female HCCs. Tip30 heterozygous deletion does not change HCC incidence in Ncoa5+/- male mice but dramatically increases HCC incidence in Ncoa5+/- female mice, accompanied by hepatic hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) overexpression. HCN3 overexpression cooperates with MYC to promote mouse HCC development, whereas Hcn3 knockout preferentially hinders HCC development in female mice. Furthermore, HCN3 amplification and overexpression occur in human HCCs and correlate 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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.