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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.
- Source :
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International journal of molecular sciences [Int J Mol Sci] 2017 Jun 15; Vol. 18 (6). Date of Electronic Publication: 2017 Jun 15. - Publication Year :
- 2017
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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.<br />Competing Interests: Peter E. Lobie and Tao Zhu have previously consulted for Perseis Therapeutics Ltd. Peter E. Lobie and Tao Zhu have direct or indirect equity interest in Wuhan Long Ke Ltd., a company which holds Chinese patent 20130446539.5. Peter E. Lobie is also named on Patent Cooperation Treaty (PCT) application numbers WO 2006/69253, WO/2008/042435, WO/2009/147530 and WO/2012/150869 and derivatives/national phase components of these applications thereof. Yi-Jun Chen, Ming-Liang You, Qing-Yun Chong, Vijay Pandey and Lan Ma declare no conflict of interest.
- Subjects :
- Apoptosis
Autocrine Communication
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Down-Regulation
Hep G2 Cells
Human Growth Hormone genetics
Humans
Liver Neoplasms metabolism
Liver Neoplasms pathology
Neoplasm Invasiveness genetics
Neoplasm Invasiveness pathology
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Carcinoma, Hepatocellular genetics
Claudin-1 genetics
Gene Expression Regulation, Neoplastic
Human Growth Hormone metabolism
Liver Neoplasms genetics
STAT3 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 18
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 28617312
- Full Text :
- https://doi.org/10.3390/ijms18061274