title: Thrombomodulin Influences the Survival of Patients with Non-Metastatic Colorectal Cancer through Epithelial-To-Mesenchymal Transition (EMT).
abstract: BACKGROUND
  Treatment resistance and metastasis are the major causes of death among patients with colorectal cancer (CRC). Approximately 20% of surgically treated patients ultimately develop metastases during the follow-up period. Currently, the TNM system is the only available prognostic test. Therefore, the identification of new markers for CRC remains important. Thrombomodulin (TM), a glycoprotein, is involved in angiogenesis and has been linked to many malignant diseases. However, the function of TM in CRC remains unclear.
  
  
  METHODS
  A total of 170 patients with CRC participated in this study. TM expression was analyzed via immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze patient outcomes, including overall survival (OS) and disease-free survival (DFS). TM expression was manipulated using shRNA or an overexpression system. Transwell migration assays, wound healing migration assays, and the xCELLigence biosensor system were used to detect cell proliferative and migratory capacities.
  
  
  RESULTS
  TM expression in the tumor tissues significantly and positively correlated with the DFS and OS of non-metastatic patients with CRC (ps = 0.036 and 0.0218, respectively). Suppression of TM expression increased the proliferation and migration of DLD-1 cells. TM overexpression reduced the cells' proliferative and migratory capacities. Cyclooxygenase (COX)-2 expression was up-regulated following TM silencing. Furthermore, the association between the migration of colon cancer cells and the levels of TM and epithelial-to-mesenchymal transition (EMT) markers (fibronectin, vimentin and ezrin) was confirmed in HT29 and DLD-1 cells.
  
  
  CONCLUSIONS
  Our study demonstrates that patients with non-metastatic CRC display low TM expression in their tumors and exhibit reduced DFS and OS. The enhanced expression of mesenchymal markers and COX-2 may be involved in the mechanisms that underlie recurrence in patients with cancer displaying low TM expression.
authors: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors: Yu-Jia
authors: YJ
authors: Chang
authors: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology,Taipei Medical University, Taipei, Taiwan, ROC.
authors: Ya-Wen
authors: YW
authors: Cheng
authors: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan, ROC.
authors: Ruo-Kai
authors: RK
authors: Lin
authors: School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.|Department of Surgery, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors: Chi-Chou
authors: CC
authors: Huang
authors: Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC.
authors: William Tzu-Liang
authors: WT
authors: Chen
authors: Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC.|Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan, ROC.
authors: Tao-Wei
authors: TW
authors: Ke
authors: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology,Taipei Medical University, Taipei, Taiwan, ROC.|Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.|Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC.|Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC.
authors: Po-Li
authors: PL
authors: Wei
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D011379:Prognosis; D016019:Survival Analysis; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D018180:Thrombomodulin; D051546:Cyclooxygenase 2