title: Versican 3'-untranslated region (3'-UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity.
abstract: This study was designed to explore the role of versican in the development of hepatocellular carcinoma (HCC). Ectopic expression of the versican 3'-untranslated region (3'-UTR) was studied as a competitive endogenous RNA for regulating miRNA functions. We used this approach to modulate the expression of versican and its related proteins in 3'-UTR transgenic mice and in the liver cancer cell line HepG2, stably transfected with the 3'-UTR or a control vector. We demonstrated that transgenic mice expressing the versican 3'-UTR developed HCC and increased expression of versican isoforms V0 and V1. HepG2 cells transfected with versican 3'-UTR displayed increased proliferation, survival, migration, invasion, colony formation, and enhanced endothelial cell growth, but decreased apoptosis. We found that versican 3'-UTR could bind to miRNAs miR-133a, miR-199a*, miR-144, and miR-431 and also interacted with CD34 and fibronectin. As a consequence, expression of versican, CD34, and fibronectin was up-regulated by ectopic transfection of the versican 3'-UTR, which was confirmed in HepG2 cells and in transgenic mice as compared with wild-type controls. Transfection with siRNAs targeting the versican 3'-UTR abolished the effects of the 3'-UTR. Taken together, these results demonstrate that versican V0 and V1 isoforms play important roles in HCC development and that versican mRNAs compete with endogenous RNAs in regulating miRNA functions.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Ling
authors.initials: L
authors.lastname: Fang
authors.forename: William W
authors.initials: WW
authors.lastname: Du
authors.forename: Xiangling
authors.initials: X
authors.lastname: Yang
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Anand
authors.initials: A
authors.lastname: Ghanekar
authors.forename: Gary
authors.initials: G
authors.lastname: Levy
authors.forename: Weining
authors.initials: W
authors.lastname: Yang
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Yee
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
authors.forename: Jim W
authors.initials: JW
authors.lastname: Xuan
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Gao
authors.forename: Feng
authors.initials: F
authors.lastname: Xie
authors.forename: Chengyan
authors.initials: C
authors.lastname: He
authors.forename: Zhaoqun
authors.initials: Z
authors.lastname: Deng
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D053675:Versicans / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D012334:RNA, Neoplasm; C508322:VCAN protein, human; C508323:Vcan protein, mouse; D053675:Versicans