Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

Abstract Prostaglandin E2 (PGE2) is involved in cholangiocarcinoma cell proliferation, migration and invasion through E prostanoid receptors, including EP1, EP2 and EP4. However, the functions and the mechanisms of those splice variants of EP3 receptors in promoting liver cancer cell growth and invasion remain to be elucidated. In our previous studies, four isoforms of EP3 receptors, EP3-4, EP3-5, EP3-6 and EP3-7 receptors, were detected in CCLP1 and HuCCT1 cells. However, the functions of these receptors in these cells have yet to be determined. It was reported that β-catenin is closely correlated with malignancy, including cholangiocarcinoma. The present study was designed to examine the effects of 4-7 isoforms of EP3 in promoting cholangiocarcinoma progression and the mechanisms by which PGE2 increases β-catenin protein via EP3 receptors. The results showed that PGE2 promotes cholangiocarcinoma progression via the upregulation of β-catenin protein, and the EP3-4 receptor pathway is mainly responsible for this regulation. These findings reveal that PGE2 upregulated the cholangiocarcinoma cell β-catenin protein through the EP3-4R/Src/EGFR/PI3K/AKT/GSK-3β pathway. The present study identified the functions of EP3 and the mechanisms by which PGE2 regulates β-catenin expression and promoted cholangiocarcinoma cell growth and invasion.