title: Thrombomodulin regulates doxorubicin sensitivity through epithelial-mesenchymal transition in non-small cell lung cancer.
abstract: Lung cancer has remained the highest about cancer-related mortality and drug resistance is involved in the recurrence of the disease. Thrombomodulin (TM) is down-regulated in several malignant tumors, but its role in drug resistance has not been elucidated in lung cancer. We aimed to investigate the role of TM in drug resistance to lung cancer.
  
  
  
  The mRNA and protein expression of TM were determined by real-time PCR and Western blot, respectively. TM expression was manipulated using siRNA or an overexpression system. The expression of epithelial-mesenchymal transition (EMT)-related markers (E-cadherin and vimentin) was detected by real-time PCR and Western blot.
  
  
  
  We found that A549 and HCC827 cells with higher TM expression were more sensitive to doxorubicin than SPC-A-1 cells with lower TM. Also, downregulation of TM reduced the doxorubicin sensitivity in A549 and HCC827 cells. On the contrary, up-regulated TM increased the doxorubicin cytotoxicity in SPC-A-1 cells. Mechanically, ectopic expression of TM elevated the expression of E-cadherin, an epithelial marker. Conversely, overexpression of TM led to reduced expression of vimentin, a mesenchymal marker, leading to the reversal of EMT in lung cancer cells. As a result, SPC-A-1 cells overexpressing TM become more sensitive to doxorubicin treatment.
  
  
  
  These findings showed that TM regulated drug sensitivity through EMT in lung cancer cells, suggesting that TM might be developed into a novel target for lung cancer patients resistant to conventional therapeutics.
authors.affiliation: Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. shun_lu@hotmail.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: B-J
authors.initials: BJ
authors.lastname: Cheng
authors.forename: S
authors.initials: S
authors.lastname: Lu
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D018180:Thrombomodulin / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018180:Thrombomodulin; D014746:Vimentin; D004317:Doxorubicin