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Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression. (Int J Mol Sci, June 2017)

Chen YJ1, You ML2, Chong QY3, Pandey V4, Zhuang QS5, Liu DX6, Ma L7, Zhu T8,9, Lobie PE10,11.

Author information
1 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore. yjchen011@gmail.com.
2 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore. csiym@nus.edu.sg.
3 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore. csicqy@nus.edu.sg.
4 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore. csivkp@nus.edu.sg.
5 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore. zhuangqiushi2007@yahoo.com.
6 School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1010, New Zealand. dong-xu.liu@aut.ac.nz.
7 Tsinghua Berkeley Shenzhen Institute (TBSI), Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China. malan@sz.tsinghua.edu.cn.
8 Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230026, China. zhut@ustc.edu.cn.
9 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230022, China. zhut@ustc.edu.cn.
10 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 119077, Singapore. csipel@nus.edu.sg.
11 Tsinghua Berkeley Shenzhen Institute (TBSI), Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China. csipel@nus.edu.sg.

Abstract
Despite progress in diagnosis and treatment of hepatocellular carcinoma (HCC), the clinical outcome is still unsatisfactory. Increased expression of human growth hormone (hGH) in HCC has been reported and is associated with poor survival outcome in HCC patients. Herein, we investigated the mechanism of the oncogenic effects of hGH in HCC cell lines. In vitro functional assays demonstrated that forced expression of hGH in these HCC cell lines promoted cell proliferation, cell survival, anchorage-independent growth, cell migration, and invasion, as previously reported. In addition, forced expression of hGH promoted cancer stem cell (CSC)-like properties of HCC cells. The increased invasive and CSC-like properties of HCC cells with forced expression of hGH were mediated by inhibition of the expression of the tight junction component CLAUDIN-1. Consistently, depletion of CLAUDIN-1 expression increased the invasive and CSC-like properties of HCC cell lines. Moreover, forced expression of CLAUDIN-1 abrogated the acquired invasive and CSC-like properties of HCC cell lines with forced expression of hGH. We further demonstrated that forced expression of hGH inhibited CLAUDIN-1 expression in HCC cell lines via signal transducer and activator of transcription 3 (STAT3) mediated inhibition of CLAUDIN-1 transcription. Hence, we have elucidated a novel hGH-STAT3-CLAUDIN-1 axis responsible for invasive and CSC-like properties in HCC. Inhibition of hGH should be considered as a therapeutic option to hinder progression and relapse of HCC.

KEYWORDS: CLAUDIN-1; STAT3; cancer stem cells; hepatocellular carcinoma; human growth hormone

PMID: 28617312