title: Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2.
abstract: Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein we examined the expression profiles of long noncoding RNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one of these, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling, and the expression of stem cell-like properties of murine cells. Interestingly, we found that human lncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expression had a poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cell cycling, and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed that lncRNA-hPVT1 up-regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and mass spectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. We confirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and that lncRNA-hPVT1 function depends on the presence of NOP2.
  
  
  CONCLUSIONS
  Our study demonstrates that the expression of many lncRNAs is up-regulated in early liver development and that the fetal liver can be used to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cell cycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects on the treatment of HCC.
authors.affiliation: Department of Medical Genetics, Second Military Medical University, Shanghai, 200433, China; Center of Reproductive Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Ji-Hang
authors.initials: JH
authors.lastname: Yuan
authors.forename: Shao-Bing
authors.initials: SB
authors.lastname: Wang
authors.forename: Fu
authors.initials: F
authors.lastname: Yang
authors.forename: Sheng-Xian
authors.initials: SX
authors.lastname: Yuan
authors.forename: Chen
authors.initials: C
authors.lastname: Ye
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Shu-Han
authors.initials: SH
authors.lastname: Sun
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010641:Phenotype; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D012359:tRNA Methyltransferases / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; C521123:PVT1 long-non-coding RNA, human; D062085:RNA, Long Noncoding; D053773:Transforming Growth Factor beta1; C065028:NOP2 protein, human; D012359:tRNA Methyltransferases