Abstract 3044: Prognostic impact of P-cadherin overexpression associated with CDH3 promoter hypomethylation in intrahepatic cholangiocarcinoma (ICC).

Abstract

Abstract Background. P-cadherin belongs to the family of classic cadherin, and accumulating evidences shows that P-cadherin is strongly associated with carcinogenesis and confers malignant phenotype of various cancers including breast, pancreatic, and colon carcinomas. Intrahepatic cholangiocarcinoma (ICC) is the second most common subtype of primary hepatobillary cancer. Despite advances in therapy, its survival rate remains poor. This study aimed to analyze P-cadherin expression and its prognostic value in Intrahepatic cholangiocarcinoma and to validate the P-cadherin gene (CDH3) promoter methylation status as the mechanism of this gene regulation. Methods. Fifty-nine patients diagnosed with ICC who underwent hepatic resection in our department were enrolled in this study. Using the paraffin-embedded tumor tissues, expression status of P-cadherin was evaluated and correlated with various clinicopathological features (age, gender, tumor markers, tumor diameter and number, stage, gross type, grade of tumor differentiation, vessel invasion, and lymph node metastases) and prognosis. Furthermore, P-cadherin expression and CDH3 promoter methylation status in 8 cholangiocarcinoma cell lines (HuCCT1, YSCCC, MEC, OZ, HuH28, RBE, SSP25, and TKKK) were analyzed. Results. In ICC tissues, 50.8% (30/59) of cases shows a high expression of P-cadherin by immunohistochemical analysis, and high expression of P-cadherin was significantly correlated with tumor diameter > 3.8 cm (p=0.0006). In multivariate analyses, P-cadherin expression was the independent prognostic factors for disease-free survival (relative risk:2.72, p=0.0138) and overall survival (relative risk:3.23 p=0.0012). Of the 8 cell lines, 3 (HuCCT1, YSCCC, OZ) were found to express P-cadherin protein and mRNA. These cell lines showed complete CDH3 promoter unmethylation. However, other cell lines showed partial methylation and unmetylation. From this result, the CDH3 promoter methylation was found to be related to the expression of P-cadherin. Conclusion. These results suggested that expression of P-cadherin is a useful prognostic marker and seems to be important in the malignant behavior in ICC. We are now conducting experiments to validate the CDH3 methylation status in the cancerous tissues and their adjacent normal counterpart, and investigating the biological role of P-cadherin in ICC. Citation Format: Keita Sakamoto, Katsunori Imai, Shigeki Nakagawa, Hirohisa Okabe, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Prognostic impact of P-cadherin overexpression associated with CDH3 promoter hypomethylation in intrahepatic cholangiocarcinoma (ICC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3044. doi:10.1158/1538-7445.AM2013-3044