title: Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling.
abstract: OBJECTIVE
  Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease.
  
  
  METHODS
  Immunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting.
  
  
  RESULTS
  CDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/β-catenin signaling.
  
  
  CONCLUSIONS
  Our results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China.
authors.forename: Hai-bo
authors.initials: HB
authors.lastname: Qiu
authors.forename: Li-yi
authors.initials: LY
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Ren
authors.forename: Zhao-lei
authors.initials: ZL
authors.lastname: Zeng
authors.forename: Wen-jing
authors.initials: WJ
authors.lastname: Wu
authors.forename: Hui-yan
authors.initials: HY
authors.lastname: Luo
authors.forename: Zhi-wei
authors.initials: ZW
authors.lastname: Zhou
authors.forename: Rui-hua
authors.initials: RH
authors.lastname: Xu
mesh_terms: D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D015996:Survival Rate; D051153:Wnt Proteins; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin
chemical_list: D014408:Biomarkers, Tumor; C490584:CDH17 protein, human; D015820:Cadherins; D009363:Neoplasm Proteins; D051153:Wnt Proteins; D051176:beta Catenin
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