title: Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma.
abstract: Angiopoietin-like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial-mesenchymal transition (EMT)-driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)-dependent early growth response protein 1 (Egr-1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients.
  
  
  
  ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor-AKT/ERK-Egr-1-Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637-1651).
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.|Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Chen
authors.affiliation: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Tsang-Chih
authors.initials: TC
authors.lastname: Kuo
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.|Graduate Program of Biotechnology in Medicine College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chi-Feng
authors.initials: CF
authors.lastname: Tseng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Jui-Ti
authors.initials: JT
authors.lastname: Ma
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Yang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shian-Ying
authors.initials: SY
authors.lastname: Sung
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan. jlsu@nhri.org.tw.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. jlsu@nhri.org.tw.|Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. jlsu@nhri.org.tw.|Department of Biotechnology, Asia University, Taichung, Taiwan. jlsu@nhri.org.tw.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
mesh_terms: D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D000077157:Sorafenib
chemical_list: C117578:ANGPTL1 protein, human; D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C529601:Angptl1 protein, mouse; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met