title: Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression.
abstract: OBJECTIVE
  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.
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors: Dong Gwang
authors: DG
authors: Lee
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Sang-Hyun
authors: SH
authors: Lee
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Jang-Seong
authors: JS
authors: Kim
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors: Jongjin
authors: J
authors: Park
authors: Department of Chemistry, Dongguk University, Seoul, Republic of Korea.
authors: Young-Lai
authors: YL
authors: Cho
authors: Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors: Koon Soon
authors: KS
authors: Kim
authors: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors: Deog Yeon
authors: DY
authors: Jo
authors: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors: Ik-Chan
authors: IC
authors: Song
authors: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors: Nayoung
authors: N
authors: Kim
authors: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors: Hwan-Jung
authors: HJ
authors: Yun
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Young-Jun
authors: YJ
authors: Park
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Seon-Jin
authors: SJ
authors: Lee
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Hee Gu
authors: HG
authors: Lee
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Kwang-Hee
authors: KH
authors: Bae
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors: Sang Chul
authors: SC
authors: Lee
authors: Department of Biochemistry, Neuromarker Resource Bank, College of Natural Sciences, Chungbuk National University, Cheongju, Republic of Korea.
authors: Sungbo
authors: S
authors: Shim
authors: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
authors: Young-Myeong
authors: YM
authors: Kim
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors: Young-Guen
authors: YG
authors: Kwon
authors: Department of Pathology, Cancer Research Institute and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Republic of Korea. Electronic address: jinmank@cnu.ac.kr.
authors: Jin-Man
authors: JM
authors: Kim
authors: Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea. Electronic address: cymed@cnu.ac.kr.
authors: Hyo Jin
authors: HJ
authors: Lee
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea. Electronic address: jekmin@kribb.re.kr.
authors: Jeong-Ki
authors: JK
authors: Min
mesh_terms: D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics* / Q000502:physiology; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D015854:Up-Regulation; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C466228:NDRG2 protein, human; D011518:Proto-Oncogene Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020794:Receptor Protein-Tyrosine Kinases; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19; D000094963:Axl Receptor Tyrosine Kinase
keywords: Epithelial-mesenchymal transition; Gallbladder carcinoma; MMP-19; NDRG2; Slug