NDRG2 Inhibits Human Cholangiocarcinoma Progression and Is Regulated by LIF/MicroRNA-181c Negative feedback Pathway.

Abstract Increasing evidence supports a role for NDRG2 deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, miR-181c and LIF in human CCA and adjacent non-tumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2, and increased levels of miR-181c and LIF compared with non-tumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c and the down-regulation of NDRG2 was due to miR-181c over-expression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad complex and LIF promoter. Down-regulation of NDRG2, over-expression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c and LIF expression is a strong predictor of prognosis in CCA patients. These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and TGF-β in CCA prevention and treatment. This article is protected by copyright. All rights reserved.