title: Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a.
abstract: OBJECTIVE
  The goal of the present study was to investigate the potential correlation between the expression level of upregulator of cell proliferation (URGCP/URG4) and the prognosis of hepatocellular carcinoma (HCC), and to examine the biological function of URGCP/URG4 in the progression of HCC, to better understand its underlying molecular mechanism in hepatic tumorigenesis.
  
  
  METHODS
  URGCP/URG4 expression was analyzed in 15 HCC cell lines, in 278 archived paraffin-embedded HCC sections, and in 10 pairs of fresh HCC tumor and para-tumor non-cancerous tissues using immunohistochemistry (IHC) and Western blotting analysis (WB). The effect of URGCP/URG4 on cell proliferation and tumorigenesis was examined in vitro and in vivo. WB and luciferase reporter analyses were performed to identify the effects of URGCP/URG4-overexpression or -knockdown on expression of cell cycle regulators and transcriptional activity of FOXO3a.
  
  
  RESULTS
  IHC results revealed an upregulation of URGCP/URG4 in all HCC cell lines and fresh HCC samples as compared with normal liver cells and para-tumor tissues, respectively. URGCP/URG4 was also expressed at a high level in 122 of the 278 (43.8%) archived HCC specimens. The expression level of URGCP/URG4 was significantly correlated with clinical staging and poor patient survival of HCC in the study cohort, and in various clinical subgroups. Strikingly, ectopic expression of URGCP/URG4 induced proliferation and anchorage-independent growth of HCC cells, while silencing of URGCP/URG4 had the opposite effect. Furthermore, URGCP/URG4 overexpression in HCC cells increased cellular entry into the G1/S transitional phase, associated with downregulation of p27(Kip1) and p21(Cip1) and upregulation of cyclin D1. These effects were accompanied by enhanced Akt activity and reduced FOXO3a transcriptional activity.
  
  
  CONCLUSIONS
  URGCP/URG4 plays an important role in promoting proliferation and tumorigenesis of HCC and may represent a novel prognostic biomarker and therapeutic target for this disease.
authors: Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
authors: Chan
authors: C
authors: Xie
authors: Li-bing
authors: LB
authors: Song
authors: Jue-heng
authors: JH
authors: Wu
authors: Jun
authors: J
authors: Li
authors: Jing-ping
authors: JP
authors: Yun
authors: Jia-ming
authors: JM
authors: Lai
authors: Dong-ying
authors: DY
authors: Xie
authors: Bing-liang
authors: BL
authors: Lin
authors: Yun-fei
authors: YF
authors: Yuan
authors: Mengfeng
authors: M
authors: Li
authors: Zhi-liang
authors: ZL
authors: Gao
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C530104:CCND1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C470990:URGCP protein, human; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases