Jiabei Wang1, Changming Xie1, Shangha Pan2, Yingjian Liang1, Jihua Han1, Yaliang Lan1, Jing Sun1, Keyu Li1, Boshi Sun1, Guangchao Yang1, Huawen Shi1, Yuejin Li1, Ruipeng Song1, Xirui Liu1, Mingxi Zhu1, Dalong Yin1, Huanlai Wang3, Xuan Song1, Zhaoyang Lu1, Hongchi Jiang1, Tongsen Zheng4, Lianxin Liu5,6. 1. Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China. 2. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China. 3. Department of General Surgery, Qiqihaer City Hospital of Traditional Chinese Medicine, Qiqihaer, China. 4. Department of Gastrointestinal Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China. zhengtongsen@hotmail.com. 5. Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China. liulianxin@ems.hrbmu.edu.cn. 6. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China. liulianxin@ems.hrbmu.edu.cn.
Abstract
Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the 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 nontumor 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 attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression 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. CONCLUSION: 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 transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).
Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in humancholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the 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 nontumor 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 attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression 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. CONCLUSION: 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 transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622).
Authors: Lindsey Kennedy; Laura Hargrove; Jennifer Demieville; Nicole Francis; Rowan Seils; Sara Villamaria; Heather Francis Journal: F1000Res Date: 2017-10-09