Recommended Citation
Zhang Y, Liu X, Sun K, Luo Y, Yang J, Li A, Kiupel M, Fenske S, Biel M, Mi QS, Wang H, and Xiao H. Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner. Cell Rep 2023; 42(10):113157.
Document Type
Article
Publication Date
10-31-2023
Publication Title
Cell Rep
Abstract
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.
Medical Subject Headings
Animals; Female; Humans; Male; Mice; Carcinoma, Hepatocellular; Cyclic Nucleotide-Gated Cation Channels; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Liver Neoplasms; Nuclear Receptor Coactivators; Transcription Factors
PubMed ID
37733590
Volume
42
Issue
10
First Page
113157
Last Page
113157
