title: Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common and malignant cancers. The HCC incidence gets a strong sexual dimorphism as men are the major sufferers in this disaster. Although several studies have uncovered the presentative correlation between the axis of androgen/androgen receptor (AR) and HCC incidence, the mechanism is still largely unknown. Cancer stem cells (CSCs) are a small subgroup of cancer cells contributing to multiple tumors malignant behaviors, which play an important role in oncogenesis of various cancers including HCC. However, whether androgen/AR axis involves in regulation of HCC cells stemness remains unclear. Our previous study had identified that the pluripotency factor Nanog is not only a stemness biomarker, but also a potent regulator of CSCs in HCC. In this study, we revealed androgen/AR axis can promote HCC cells stemness by transcriptional activation of Nanog expression through directly binding to its promoter. In HCC tissues, we found that AR expression was abnormal high and got correlation with Nanog. Then, by labeling cellular endogenous Nanog with green fluorescent protein (GFP) through CRISPR/Cas9 system, it verified the co-localization of AR and Nanog in HCC cells. With in vitro experiments, we demonstrated the axis can promote HCC cells stemness, which effect is in a Nanog-dependent manner and through activating its transcription. And the xenografted tumor experiments confirmed the axis effect on tumorigenesis facilitation in vivo. Above all, we revealed a new sight of androgen/AR axis roles in HCC and provided a potential way for suppressing the axis in HCC therapy.
authors.affiliation: Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lupin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.|Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Shan
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yan
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Wenxu
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Huicheng
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liang
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein / Q000096:biosynthesis*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000728:Androgens; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D011944:Receptors, Androgen
keywords: CRISPR/Cas9; Nanog; androgen/androgen receptor axis; cancer stem cells; hepatocellular carcinoma