Oncotarget

Research Papers:

Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma

Lupin Jiang, Juanjuan Shan, Junjie Shen, Yanzhou Wang, Ping Yan, Limei Liu, Wenxu Zhao, Yanmin Xu, Wei Zhu, Li Su, Jun Chen, Feifei Cheng, Hong Yao, Huicheng Xu, Cheng Qian and Zhiqing Liang _

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Oncotarget. 2016; 7:36814-36828. https://doi.org/10.18632/oncotarget.9192

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Abstract

Lupin Jiang1, Juanjuan Shan2,3, Junjie Shen2, Yanzhou Wang1, Ping Yan1, Limei Liu2, Wenxu Zhao2, Yanmin Xu2, Wei Zhu2, Li Su2, Jun Chen2, Feifei Cheng2, Hong Yao1, Huicheng Xu1, Cheng Qian2, Zhiqing Liang1

1Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China

2Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China

3Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China

Correspondence to:

Zhiqing Liang, email: [email protected]

Cheng Qian, email: [email protected]

Keywords: hepatocellular carcinoma, androgen/androgen receptor axis, Nanog, cancer stem cells, CRISPR/Cas9

Received: February 03, 2016    Accepted: April 16, 2016    Published: May 5, 2016

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.


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