title: Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1α activity and inhibiting epithelial-mesenchymal transition.
abstract: 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.
authors.affiliation: Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.|Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.|Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.
authors.forename: Tong-Hong
authors.initials: TH
authors.lastname: Wang
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan.
authors.forename: Yong-Shiang
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan.
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Kung-Hao
authors.initials: KH
authors.lastname: Liang
authors.affiliation: Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan.
authors.forename: Tzong-Ming
authors.initials: TM
authors.lastname: Shieh
authors.affiliation: Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.|Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.|Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan.
authors.forename: Chuen
authors.initials: C
authors.lastname: Hsueh
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000302:isolation & purification / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015331:Cohort Studies; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000302:isolation & purification / Q000378:metabolism*; D046888:Tissue Array Analysis; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D062085:RNA, Long Noncoding
keywords: hepatocellular carcinoma (HCC); long noncoding RNA (lncRNA); metastasis