Anti-cadherin-17 antibody modulates beta-catenin signaling and tumorigenicity of hepatocellular carcinoma

Yonggang Wang; Felix H Shek; Kwong F Wong; Ling Xiao Liu; Xiao Qian Zhang; Yi Yuan; Ester Khin; Mei-Yu Hu; Jian Hua Wang; Ronnie T P Poon; Wanjin Hong; Nikki P Lee; John M Luk

doi:10.1371/journal.pone.0072386

Anti-cadherin-17 antibody modulates beta-catenin signaling and tumorigenicity of hepatocellular carcinoma

PLoS One. 2013 Sep 11;8(9):e72386. doi: 10.1371/journal.pone.0072386. eCollection 2013.

Authors

Yonggang Wang¹, Felix H Shek, Kwong F Wong, Ling Xiao Liu, Xiao Qian Zhang, Yi Yuan, Ester Khin, Mei-Yu Hu, Jian Hua Wang, Ronnie T P Poon, Wanjin Hong, Nikki P Lee, John M Luk

Affiliation

¹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / pharmacology*
Antibodies, Monoclonal / therapeutic use
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Cadherins / immunology
Cadherins / metabolism
Carcinogenesis / drug effects
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / metabolism
Caspase 8 / metabolism
Caspase 9 / metabolism
Cell Line, Tumor
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / metabolism
Mice
Mice, Inbred BALB C
Tumor Burden / drug effects
Wnt Signaling Pathway / drug effects*
Xenograft Model Antitumor Assays
beta Catenin / metabolism

Substances

Antibodies, Monoclonal
Antineoplastic Agents
CDH17 protein, human
CTNNB1 protein, human
Cadherins
beta Catenin
CASP8 protein, human
CASP9 protein, human
Caspase 8
Caspase 9

Grants and funding

The study was supported in part by grant the National Research Foundation Proof-of-Concept Fund (NRF2009NRF-POC002-97) and the Hong Kong Research Grants Council General Research Fund (J.M.L.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.