Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner

Yueqi Zhang; Xinhui Liu; Kairui Sun; Yue Luo; Jack Yang; Aimin Li; Matti Kiupel; Stefanie Fenske; Martin Biel; Qing-Sheng Mi; Hongbing Wang; Hua Xiao

doi:10.1016/j.celrep.2023.113157

Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner

Cell Rep. 2023 Oct 31;42(10):113157. doi: 10.1016/j.celrep.2023.113157. Epub 2023 Sep 20.

Authors

Yueqi Zhang¹, Xinhui Liu², Kairui Sun³, Yue Luo², Jack Yang⁴, Aimin Li², Matti Kiupel⁵, Stefanie Fenske⁶, Martin Biel⁶, Qing-Sheng Mi⁷, Hongbing Wang⁴, Hua Xiao⁸

Affiliations

¹ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
² Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China.
³ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
⁴ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
⁵ Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
⁶ Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians Universität München, 81377 München, Germany.
⁷ Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI 48202, USA; Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202, USA.
⁸ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA. Electronic address: xiaoh@msu.edu.

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.

Keywords: CP: Cancer; HCN3; NCOA5; TIP30; liver cancer; sex disparity in cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / pathology
Cyclic Nucleotide-Gated Cation Channels / genetics
Cyclic Nucleotide-Gated Cation Channels / metabolism
Female
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
Liver Neoplasms* / genetics
Liver Neoplasms* / pathology
Male
Mice
Nuclear Receptor Coactivators / genetics
Transcription Factors / metabolism

Substances

Cyclic Nucleotide-Gated Cation Channels
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
NCOA5 protein, mouse
Nuclear Receptor Coactivators
Transcription Factors
HCN3 protein, human
HCN3 protein, mouse

Grants and funding

R01 CA188305/CA/NCI NIH HHS/United States