title: N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway.
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.
  
  
  
  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.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Changming
authors.initials: C
authors.lastname: Xie
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Yaliang
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Keyu
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Boshi
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Huawen
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Xirui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Dalong
authors.initials: D
authors.lastname: Yin
authors.affiliation: Department of General Surgery, Qiqihaer City Hospital of Traditional Chinese Medicine, Qiqihaer, China.
authors.forename: Huanlai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China.
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Gastrointestinal Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China. zhengtongsen@hotmail.com.
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.affiliation: 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.|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.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology*; D018281:Cholangiocarcinoma / Q000209:etiology*; D018450:Disease Progression; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000502:physiology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053605:Leukemia Inhibitory Factor; C000608460:MIRN-181 microRNA, human; D035683:MicroRNAs; C466228:NDRG2 protein, human; C485172:Ndr2 protein, mouse; D011506:Proteins; D025521:Tumor Suppressor Proteins; C529100:mirn181 microRNA, mouse