title: Significance of P-cadherin overexpression and possible mechanism of its regulation in intrahepatic cholangiocarcinoma and pancreatic cancer.
abstract: It has become evident that P-cadherin, one of the classical cadherins, contributes to the malignant behavior of several types of cancer. In this study, we analyzed the expression of P-cadherin and its clinicopathological and prognostic values in intrahepatic cholangiocarcinoma (ICC) and pancreatic cancer. Furthermore, we investigated the functional role of P-cadherin in these cancer cells by knockdown and overexpression in vitro and by analyzing the correlation between the P-cadherin expression and its promoter methylation status. Thirty of 59 ICC cases (51%) and 36 of 73 pancreatic cancer cases (49%) stained positive for P-cadherin with mainly membranous distribution in tumor cells by immunohistochemistry. P-cadherin expression was significantly correlated with several clinicopathological factors, which reflect tumor behavior, and was identified as an independent adverse prognostic factor for disease-free survival in patients with ICC (relative risk [RR] 2.93, P = 0.04) and pancreatic cancer (RR 2.68, P = 0.005) via multivariate analyses. P-cadherin downregulation by siRNA suppressed migration and invasion, and P-cadherin overexpression induced the opposite effects in both ICC and pancreatic cancer cells, without any effects on cell proliferation. P-cadherin expression was related to its promoter methylation status in both cell lines and cancer tissues. In summary, P-cadherin overexpression may serve as a useful biomarker of invasive phenotype and poor prognosis; P-cadherin expression was found to be regulated by its promoter methylation. These results suggest that P-cadherin represents a novel therapeutic target for the treatment of ICC and pancreatic cancer.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Katunobu
authors.initials: K
authors.lastname: Taki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Okabe
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Chikamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Ishiko
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology*; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins
keywords: Intrahepatic cholangiocarcinoma; P-cadherin; invasiveness and migration; pancreatic cancer; promoter hypomethylation