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
Affiliations
Yueqi Zhang
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA
Xinhui Liu
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
Kairui Sun
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA
Yue Luo
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
Jack Yang
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
Aimin Li
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong 510315, China
Matti Kiupel
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA
Stefanie Fenske
Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians Universität München, 81377 München, Germany
Martin Biel
Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians Universität München, 81377 München, Germany
Qing-Sheng Mi
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
Hongbing Wang
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
Hua Xiao
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA; Corresponding author
Summary: 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.
