title: Anti-cadherin-17 antibody modulates beta-catenin signaling and tumorigenicity of hepatocellular carcinoma.
abstract: Cadherin-17 (CDH17) is an oncofetal molecule associated with poor prognostic outcomes of hepatocellular carcinoma (HCC), for which the treatment options are very limited. The present study investigates the therapeutic potential of a monoclonal antibody (Lic5) that targets the CDH17 antigen in HCC. In vitro experiments showed Lic5 could markedly reduce CDH17 expression in a dose-dependent manner, suppress β-catenin signaling, and induce cleavages of apoptotic enzymes caspase-8 and -9 in HCC cells. Treatment of animals in subcutaneous HCC xenograft model similarly demonstrated significant tumor growth inhibition (TGI) using Lic5 antibody alone (5 mg/kg, i.p., t.i.w.; ca.60-65% TGI vs. vehicle at day 28), or in combination with conventional chemotherapy regimen (cisplatin 1 mg/kg; ca. 85-90% TGI). Strikingly, lung metastasis was markedly suppressed by Lic5 treatments. Immunohistochemical and western blot analyses of xenograft explants revealed inactivation of the Wnt pathway and suppression of Wnt signaling components in HCC tissues. Collectively, anti-CDH17 antibody promises as an effective biologic agent for treating malignant HCC.
authors.affiliation: Department of Oncology, Affiliated 6th People's Hospital, Shanghai Jiao Tong University, Shanghai, China ; Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong ; Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Wang
authors.forename: Felix H
authors.initials: FH
authors.lastname: Shek
authors.forename: Kwong F
authors.initials: KF
authors.lastname: Wong
authors.forename: Ling Xiao
authors.initials: LX
authors.lastname: Liu
authors.forename: Xiao Qian
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Yuan
authors.forename: Ester
authors.initials: E
authors.lastname: Khin
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Hu
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Wang
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.forename: Nikki P
authors.initials: NP
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000276:immunology / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C490584:CDH17 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9
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