title: Proteomics-based identification of secreted protein dihydrodiol dehydrogenase 2 as a potential biomarker for predicting cisplatin efficacy in advanced NSCLC patients.
abstract: OBJECTIVE
  Cisplatin is the major agent in the standard first-line chemotherapy for NSCLC. However, only a small portion of patients achieve a tumor response to cisplatin-based chemotherapy and eventually develop acquired resistance. The aim of this study was to identify potential biomarkers that could predict the efficacy of cisplatin.
  
  
  METHODS
  Human lung adenocarcinoma cell line A549 was exposed to cisplatin for development of a resistant cell line, A549/DDP, and cisplatin-sensitivity was tested through the MTT assay. The global protein profiles from A549 and A549/DDP were compared using a proteomic approach. Western blot, real-time PCR and immunohistochemistry validated the expression of DDH2 in cell lines and tumor xenografts. Serum levels of DDH2 were measured by ELISA in 105 NSCLC patients treated with cisplatin-based chemotherapy.
  
  
  RESULTS
  The resistance of A549/DDP to cisplatin was 8.07-fold higher than that of A549 cells. Proteomic approach identified eight differentially (>5-fold) expressed proteins. Among them, secreted protein DDH2 was further investigated and it was found overexpressed through the method of Western blot, real-time PCR in cell lines, consistent with immunohistochemistry validation in xenograft. Clinical research showed that baseline serum DDH2 level in the patients with a progression disease was significantly higher than the patients of response or stable disease (9.036 vs. 3.529 and 3.982 ng/mL, P<0.001) and serum DDH2 levels were significantly increased after cisplatin-based doublet chemotherapy (5.515 vs. 12.935 vs. 18.406 ng/mL P<0.001, respectively).
  
  
  CONCLUSIONS
  DDH2 expression might be a potential predictor and monitor of cisplatin efficacy in advanced NSCLC patients.
authors.affiliation: Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Kuang
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Xuefei
authors.initials: X
authors.lastname: Li
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Ren
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Jiayu
authors.initials: J
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Yinmin
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D040901:Proteomics; D014158:Transcription, Genetic; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002945:Cisplatin; D006913:Hydroxysteroid Dehydrogenases; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)