Downregulated expression of PHLDA1 protein is associated with a malignant phenotype of cholangiocarcinoma.

Cholangiocarcinoma is one of the most aggressive types of malignancy, and is associated with poor patient prognosis. Recent findings suggest that a decrease in pleckstrin homology-like domain family A, member 1 (PHLDA1) expression is significant in the induction of cell migration and tumor invasion. The clinicopathological significance of the expression of PHLDA1, and its potential correlation with the expression of CD133 in cholangiocarcinoma have remained to be elucidated. In the present study, PHLDA1 protein expression was investigated by immunohistochemical analysis of 218 cholangiocarcinoma tissue samples, as well as 30 para-neoplastic and 20 normal bile ducts. The expression status of PHLDA1 and CD133 was determined, and these results were analyzed against the age, gender, tumor location and size, histological grade, clinical stage and overall mean survival time of the patients. The expression of PHLDA1 protein was markedly decreased in 35.3% of cholangiocarcinomas, compared with that of the para-neoplastic and normal cholangiocytes. Carcinomas with loss of expression of PHLDA1 were significantly correlated with the tumor site (P=0.001), histological grade (P=0.020) and clinical stage (P=0.0001), but not with age (P=0.085), gender (P=0.456) or size (P=0.413), respectively. Kaplan-Meier survival analysis indicated that the loss of expression of PHLDA1 was significantly correlated with the overall survival time (Log rank=193.861; P=0.0001). Furthermore, the expression of PHLDA1 was found to be inversely correlated with the expression of CD133 (γ=-0.142; P=0.036). These findings suggested that the decreased expression of PHLDA1 may be significant in the carcinogenesis and progression of cholangiocarcinoma, and may represent a novel adjunct marker of disease prognosis.