title: MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma.
abstract: BACKGROUND
  Increasing evidence indicates that deregulation of microRNAs (miRNAs) is involved in tumorigenesis. Downregulation of microRNA-503 has been observed in various types of diseases, including cancer. However, the biological function of miR-503 in hepatocellular carcinoma (HCC) is still largely unknown. In this study we aimed to elucidate the prognostic implications of miR-503 in HCC and its pathophysiologic role.
  
  
  METHODS
  Quantitative reverse transcriptase polymerase chain reaction was used to evaluate miR-503 expression in HCC tissues and cell lines. Western blotting was performed to evaluate the expression of the miR-503 target genes. In vivo and in vitro assays were performed to evaluate the function of miR-503 in HCC. Luciferase reporter assay was employed to validate the miR-503 target genes.
  
  
  RESULTS
  miR-503 was frequently downregulated in HCC cell lines and tissues. Low expression levels of miR-503 were associated with enhanced malignant potential such as portal vein tumor thrombi, histologic grade, TNM stage, AFP level and poor prognosis. Multivariate analysis indicated that miR-503 downregulation was significantly associated with worse overall survival of HCC patients. Functional studies showed miR-503 suppressed the proliferation of HCC cells by induction of G1 phase arrest through Rb-E2F signaling pathways, and thus may function as a tumor suppressor. Further investigation characterized two cell cycle-related molecules, cyclin D3 and E2F3, as the direct miR-503 targets.
  
  
  CONCLUSIONS
  Our data highlight an important role for miR-503 in cell cycle regulation and in the molecular etiology of HCC, and implicate the potential application of miR-503 in prognosis prediction and miRNA-based HCC therapy.
authors: Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, Zhejiang, P.R. China.
authors: Fenqiang
authors: F
authors: Xiao
authors: Wu
authors: W
authors: Zhang
authors: Liming
authors: L
authors: Chen
authors: Fei
authors: F
authors: Chen
authors: Haiyang
authors: H
authors: Xie
authors: Chunyang
authors: C
authors: Xing
authors: Xiaobo
authors: X
authors: Yu
authors: Songming
authors: S
authors: Ding
authors: Kangjie
authors: K
authors: Chen
authors: Haijun
authors: H
authors: Guo
authors: Jun
authors: J
authors: Cheng
authors: Shusen
authors: S
authors: Zheng
authors: Lin
authors: L
authors: Zhou
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D056743:Cyclin D3 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D050699:E2F3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C534696:CCND3 protein, human; D056743:Cyclin D3; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D016160:Retinoblastoma Protein
references: Nat Genet. 2005 May;37(5):495-500
references: 15806104
references: Mol Biol Cell. 2010 Jul 1;21(13):2138-49
references: 20462953
references: Cancer Prev Res (Phila). 2012 Apr;5(4):665-74
references: 22318752
references: Cell. 2003 Apr 4;113(1):25-36
references: 12679032
references: Cancer Cell. 2006 Mar;9(3):189-98
references: 16530703
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53
references: 18158296
references: Nat Rev Cancer. 2006 Apr;6(4):259-69
references: 16557279
references: Hepatology. 2009 Jul;50(1):113-21
references: 19441017
references: Science. 2004 Jan 2;303(5654):83-6
references: 14657504
references: Cell. 2005 Jan 14;120(1):15-20
references: 15652477
references: Gastroenterology. 2007 Jun;132(7):2557-76
references: 17570226
references: Childs Nerv Syst. 2009 Jan;25(1):13-20
references: 18818933
references: Leukemia. 2010 Feb;24(2):460-6
references: 19956200
references: Hepatology. 2008 Dec;48(6):2047-63
references: 19003900
references: Carcinogenesis. 2012 May;33(5):1113-20
references: 22362728
references: Acta Haematol. 2012;128(3):187-9
references: 22890417
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004
references: 14973191
references: Circulation. 2011 Jan 25;123(3):282-91
references: 21220732
references: Oncogene. 2005 Apr 18;24(17):2909-15
references: 15838524
references: Cancer Res. 2007 Sep 15;67(18):8699-707
references: 17875710
references: BMC Cancer. 2009 Jun 18;9:194
references: 19538740
references: Nature. 2006 Jan 19;439(7074):283-9
references: 16421561
references: Oncogene. 2006 Apr 20;25(17):2537-45
references: 16331254
references: Cancer Res. 2009 Feb 1;69(3):1135-42
references: 19155302
references: Nature. 2005 Jun 9;435(7043):834-8
references: 15944708
references: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references: 15761078
references: Nucleic Acids Res. 2008 Sep;36(16):5391-404
references: 18701644
references: Nature. 2004 Sep 16;431(7006):350-5
references: 15372042
references: Cell. 2004 Jan 23;116(2):281-97
references: 14744438
references: Nature. 2004 Nov 18;432(7015):298-306
references: 15549091
references: J Surg Oncol. 2011 Sep 1;104(3):278-83
references: 21495032
references: Nat Rev Cancer. 2006 Nov;6(11):857-66
references: 17060945