Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1α activity and inhibiting epithelial-mesenchymal transition
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Tong-Hong Wang1,2,3, Cheng-Chia Yu4,5,6, Yong-Shiang Lin7, Tse-Ching Chen7, Chau-Ting Yeh8, Kung-Hao Liang8, Tzong-Ming Shieh9, Chi-Yuan Chen2,3, Chuen Hsueh1,7
1Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
2Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
3Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
4School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
5Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
6Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
7Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
8Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
9Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan
Tong-Hong Wang, email: firstname.lastname@example.org
Chuen Hsueh, email: email@example.com
Keywords: long noncoding RNA (lncRNA), hepatocellular carcinoma (HCC), metastasis
Received: January 20, 2016 Accepted: May 09, 2016 Published: May 26, 2016
Recently, increasing numbers of long noncoding RNAs (lncRNAs), with both oncogenic and tumor-suppressive potential, have been found to be aberrantly expressed in various human cancers. However, the function of lncRNAs in hepatocellular carcinoma (HCC) progression remains largely unknown. In this study, we performed a comprehensive microarray analysis of lncRNA expression using human HCC specimens. After validation in 119 human HCC tissues, we identified a novel tumor suppressor lncRNA, CPS1 intronic transcript 1 (CPS1-IT1). To elucidate the clinical significance of CPS1-IT1 in HCC, correlations between CPS1-IT1 levels, clinical parameters, and survival outcomes were analyzed. In vitro and in vivo functional assays were also performed to dissect the potential underlying mechanisms. Expression of CPS1-IT1 was significantly decreased in 73% of HCC tissues, and patients with low CPS1-IT1 expression had poor survival outcomes. Furthermore, in vitro functional assays indicated that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities through reduced Hsp90 binding to and activation of HIF-1α, thereby suppressing the epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor suppressor role of CPS1- IT1 via decreased tumor growth and metastasis. In conclusion, lncRNA CPS1-IT1 acts as a tumor suppressor in HCC by reducing HIF-1α activation and suppressing EMT. The findings of this study establish a function for CPS1-IT1 in HCC progression and suggest its potential as a new prognostic biomarker and target for HCC therapy.
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