Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression

Dong Gwang Lee, Sang Hyun Lee, Jang Seong Kim, Jongjin Park, Young Lai Cho, Koon Soon Kim, Deog Yeon Jo, Ik Chan Song, Nayoung Kim, Hwan Jung Yun, Young Jun Park, Seon Jin Lee, Hee Gu Lee, Kwang Hee Bae, Sang Chul Lee, Sungbo Shim, Young Myeong Kim, Young Guen Kwon, Jin Man Kim, Hyo Jin LeeJeong Ki Min

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Background & Aims Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and one of the most lethal forms of human cancer. However, there is limited information about the molecular pathogenesis of GBC. Here, we examined the functional role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) and the underlying molecular mechanisms of disease progression in GBC. Methods Clinical correlations between NDRG2 expression and clinicopathological factors were determined by immunohistochemical analysis of tumor tissues from 86 GBC patients. Biological functions of NDRG2 and NDRG2-mediated signaling pathways were determined in GBC cell lines with NDRG2 knockdown or overexpression. Results Loss of NDRG2 expression was an independent predictor of decreased survival and was significantly associated with a more advanced T stage, higher cellular grade, and lymphatic invasion in patients with GBC. GBC cells with loss of NDRG2 expression showed significantly enhanced proliferation, migration, and invasiveness in vitro, and tumor growth and metastasis in vivo. Loss of NDRG2 induced the expression of matrix metalloproteinase-19 (MMP-19), which regulated the expression of Slug at the transcriptional level. In addition, MMP-19-induced Slug, increased the expression of a receptor tyrosine kinase, Axl, which maintained Slug expression through a positive feedback loop, and stabilized epithelial-mesenchymal transition of GBC cells. Conclusions The results of our study help to explain why the loss of NDRG2 expression is closely correlated with malignancy of GBC. These results strongly suggest that NDRG2 could be a favorable prognostic indicator and promising target for therapeutic agents against GBC.

Original languageEnglish
Pages (from-to)1429-1439
Number of pages11
JournalJournal of Hepatology
Volume63
Issue number6
DOIs
Publication statusPublished - 2015 Dec 1

Bibliographical note

Funding Information:
This study was supported by grants from the Korea Research Institute of Bioscience and Biotechnology, by the National Research Foundation of Korea , which was funded by the Ministry of Science, Information & Communication Technology and Future Planning (grants NRF-2013M3A9B6046566 , NRF-2014R1A1A2059765 , 2015R1A2A2A01007743 , and 2015M3A9D7029882 ), and by the Creative Allied Project and National Agenda Project through the National Research Council of Science and Technology .

All Science Journal Classification (ASJC) codes

  • Hepatology

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