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

• Published in: PloS one Vol. 8; no. 9; p. e72386
• Main Authors: Wang, Yonggang, Shek, Felix H, Wong, Kwong F, Liu, Ling Xiao, Zhang, Xiao Qian, Yuan, Yi, Khin, Ester, Hu, Mei-Yu, Wang, Jian Hua, Poon, Ronnie T P, Hong, Wanjin, Lee, Nikki P, Luk, John M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.09.2013; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antigens; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; beta Catenin - metabolism; Biological effects; Biology; Breast cancer; Cadherin; Cadherins; Cadherins - immunology; Cadherins - metabolism; Cancer metastasis; Carcinogenesis - drug effects; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Caspase; Caspase 8 - metabolism; Caspase 9 - metabolism; Caspase-8; Cell adhesion & migration; Cell Line, Tumor; Chemotherapy; Cisplatin; Deactivation; Enzymes; Epidermal growth factor; Explants; Growth inhibition; Health aspects; Hepatocellular carcinoma; Hospitals; Humans; Immunoglobulins; Inactivation; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Lungs; Metastases; Mice; Mice, Inbred BALB C; Monoclonal antibodies; Oncology; Pharmacology; Prostate; Signaling; Surgery; Tissues; Tumor Burden - drug effects; Tumorigenesis; Tumorigenicity; Tumors; Vascular endothelial growth factor; Wnt protein; Wnt Signaling Pathway - drug effects; Xenograft Model Antitumor Assays; Xenografts; β-Catenin; Hong Kong China; China; Singapore
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072386

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.