title: Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma.
abstract: Hepatocellular carcinoma (HCC) is a lethal malignancy for which there are no effective therapies. To develop rational therapeutic approaches for treating this disease, we are performing proof-of-principle studies targeting molecules crucial for the development of HCC. Here, we show that cadherin-17 (CDH17) adhesion molecule is up-regulated in human liver cancers and can transform premalignant liver progenitor cells to produce liver carcinomas in mice. RNA interference-mediated knockdown of CDH17 inhibited proliferation of both primary and highly metastatic HCC cell lines in vitro and in vivo. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt signaling, because growth inhibition and cell death were accompanied by relocalization of beta-catenin to the cytoplasm and a concomitant reduction in cyclin D1 and an increase in retinoblastoma.
  
  
  CONCLUSIONS
  Our results identify CDH17 as a novel oncogene in HCC and suggest that CDH17 is a biomarker and attractive therapeutic target for this aggressive malignancy.
authors.affiliation: Department of Surgery and Center for Cancer Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Ling Xiao
authors.initials: LX
authors.lastname: Liu
authors.forename: Nikki P
authors.initials: NP
authors.lastname: Lee
authors.forename: Vivian W
authors.initials: VW
authors.lastname: Chan
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.forename: Xiao Lin
authors.initials: XL
authors.lastname: Wang
authors.forename: Michelle Z
authors.initials: MZ
authors.lastname: Xu
authors.forename: Terence K
authors.initials: TK
authors.lastname: Lee
authors.forename: Irene O
authors.initials: IO
authors.lastname: Ng
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
authors.forename: Hsiang-fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Wang
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C490584:CDH17 protein, human; D015820:Cadherins; C490585:Cdh17 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin
references.citation: J Cell Biol. 1994 Jun;125(6):1353-69
references.pmid: 8207063
references.citation: Biochem Biophys Res Commun. 2004 Jun 25;319(2):562-8
references.pmid: 15178443
references.citation: Clin Oncol (R Coll Radiol). 2008 May;20(4):275-83
references.pmid: 18353622
references.citation: Gut. 2001 Jul;49(1):73-81
references.pmid: 11413113
references.citation: Mutat Res. 2008 May 31;653(1-2):6-13
references.pmid: 18467159
references.citation: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):483-9
references.pmid: 15701831
references.citation: J Clin Invest. 2006 Jun;116(6):1582-95
references.pmid: 16710476
references.citation: Cancer Sci. 2003 May;94(5):425-30
references.pmid: 12824888
references.citation: Br J Cancer. 2008 Jan 15;98(1):4-8
references.pmid: 18182973
references.citation: Ann Surg Oncol. 2007 Jan;14(1):94-9
references.pmid: 17063305
references.citation: Cold Spring Harb Symp Quant Biol. 2005;70:251-61
references.pmid: 16869761
references.citation: World J Gastroenterol. 2001 Oct;7(5):630-6
references.pmid: 11819844
references.citation: Biochem Biophys Res Commun. 2003 Nov 21;311(3):618-24
references.pmid: 14623315
references.citation: Cancer Genet Cytogenet. 2004 Jan 1;148(1):80-4
references.pmid: 14697646
references.citation: J Mol Biol. 2007 Jul 6;370(2):220-30
references.pmid: 17512947
references.citation: Apoptosis. 2006 Jul;11(7):1215-29
references.pmid: 16699959
references.citation: Int J Cancer. 2003 Sep 1;106(3):334-41
references.pmid: 12845670
references.citation: Cell. 2009 Mar 20;136(6):1136-47
references.pmid: 19303855
references.citation: Science. 1994 Apr 15;264(5157):430-3
references.pmid: 8153632
references.citation: Bioinformatics. 2007 Jul 1;23(13):i450-8
references.pmid: 17646330
references.citation: J Mol Biol. 2008 Apr 18;378(1):44-54
references.pmid: 18342884
references.citation: Cancer Lett. 2004 Aug 30;212(2):253-9
references.pmid: 15279905
references.citation: Gastroenterology. 2008 May;134(6):1752-63
references.pmid: 18471552
references.citation: Cell Mol Life Sci. 2006 Jul;63(13):1564-73
references.pmid: 16791429
references.citation: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references.pmid: 15761078
references.citation: Liver Transpl. 2004 Feb;10(2 Suppl 1):S39-45
references.pmid: 14762838
references.citation: Hepatology. 2007 Jul;46(1):200-8
references.pmid: 17596871
references.citation: Dis Colon Rectum. 2007 Nov;50(11):1873-80
references.pmid: 17828401
references.citation: J Clin Microbiol. 1987 Nov;25(11):2140-4
references.pmid: 2447120
references.citation: Hepatology. 2000 Jan;31(1):173-81
references.pmid: 10613743
references.citation: Cell. 2006 Jun 30;125(7):1253-67
references.pmid: 16814713
references.citation: Clin Cancer Res. 2006 Sep 1;12(17):5248-52
references.pmid: 16951245
references.citation: Cell. 2008 Nov 28;135(5):852-64
references.pmid: 19012953
references.citation: Proteomics. 2008 May;8(10):2136-49
references.pmid: 18425728
references.citation: Curr Opin Oncol. 2008 Jan;20(1):90-6
references.pmid: 18043262
references.citation: Virchows Arch. 2005 Oct;447(4):717-22
references.pmid: 16044349