Dong Gwang Lee1, Sang-Hyun Lee2, Jang-Seong Kim2, Jongjin Park1, Young-Lai Cho3, Koon Soon Kim4, Deog Yeon Jo5, Ik-Chan Song5, Nayoung Kim5, Hwan-Jung Yun5, Young-Jun Park2, Seon-Jin Lee2, Hee Gu Lee2, Kwang-Hee Bae2, Sang Chul Lee2, Sungbo Shim6, Young-Myeong Kim7, Young-Guen Kwon8, Jin-Man Kim9, Hyo Jin Lee10, Jeong-Ki Min11. 1. 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. 2. Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. 3. Department of Chemistry, Dongguk University, Seoul, Republic of Korea. 4. Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea. 5. Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea. 6. Department of Biochemistry, Neuromarker Resource Bank, College of Natural Sciences, Chungbuk National University, Cheongju, Republic of Korea. 7. Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea. 8. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. 9. 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. 10. Department of Internal Medicine and Cancer Research Institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea. Electronic address: cymed@cnu.ac.kr. 11. 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.
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.
BACKGROUND & AIMS:Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and one of the most lethal forms of humancancer. 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: Mitchell S von Itzstein; Michael C Burke; Rolf A Brekken; Todd A Aguilera; Herbert J Zeh; Muhammad Shaalan Beg Journal: Target Oncol Date: 2020-10 Impact factor: 4.493