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.

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: Jiabei Wang, Changming Xie, Shangha Pan, Yingjian Liang, Jihua Han, Yaliang Lan, Jing Sun, Keyu Li, Boshi Sun, Guangchao Yang, Huawen Shi, Yuejin Li, Ruipeng Song, Xirui Liu, Mingxi Zhu, Dalong Yin, Huanlai Wang, Xuan Song, Zhaoyang Lu, Hongchi Jiang, Tongsen Zheng, Lianxin Liu
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 64 Issue 5 Pg. 1606-1622 (11 2016) ISSN: 1527-3350 [Electronic] United States
• PMID: 27533020 (Publication Type: Journal Article)
• Copyright: © 2016 by the American Association for the Study of Liver Diseases.

Chemical References

• Adaptor Proteins, Signal Transducing
• Leukemia Inhibitory Factor
• MIRN-181 microRNA, human
• MicroRNAs
• NDRG2 protein, human
• Ndr2 protein, mouse
• Proteins
• Tumor Suppressor Proteins
• mirn181 microRNA, mouse

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Bile Duct Neoplasms (etiology)
• Cholangiocarcinoma (etiology)
• Disease Progression
• Feedback, Physiological
• Female
• Humans
• Leukemia Inhibitory Factor (physiology)
• Male
• Mice
• MicroRNAs (physiology)
• Middle Aged
• Proteins (physiology)
• Signal Transduction
• Tumor Suppressor Proteins (physiology)