Estrogen is increased in male cholangiocarcinoma patients’ serum and stimulates invasion in cholangiocarcinoma cell lines in vitro

Abstract

Cholangiocarcinoma is defined as a chronic liver disease with altered estrogen metabolism and could result in estrogen retention. Estrogenic response was known as a promoting factor in progression of some cancer. In this study, we determined the significant increase of estrogen level in cholangiocarcinoma patients' sera. The estrogen levels in cholangiocarcinoma patients' sera were measured and correlated with clinical presentations. Estrogen receptor-α expressions in cholangiocarcinoma tissues were detected by immunohistochemistry method. KKU-100 and KKU-M213 cholangiocarcinoma cell lines were treated with 17β-estradiol and tested the proliferative and invasive effects. The estrogen levels showed positive correlations with serum bilirubin and alkaline phosphatase and a negative correlation with albumin. This study also showed an association with shorter survival times when patients with low and high serum estrogen levels were compared. In vitro studies demonstrated the effect of estrogen on cell proliferation and invasion in dose-dependent manners, which could be inhibited by tamoxifen, a clinical used estrogen antagonist. Invasion showed an association with the TFF1 gene expression and could be inhibited by small interfering RNA against TFF1 gene. Estrogen receptor-α was the main estrogen receptor that response to 17β-estradiol stimulation. TFF1 trefoil protein could be one of the effectors for estrogen-induced invasion in cholangiocarcinoma via the estrogen receptor-α. These findings could lead to an understanding of the mechanism of cholangiocarcinoma progression.