title: GTSE1 expression represses apoptotic signaling and confers cisplatin resistance in gastric cancer cells.
abstract: BACKGROUND
  Platinum based therapy is commonly used in the treatment of advanced gastric cancer. However, resistance to chemotherapy is a major challenge that causes marked variation in individual response rate and survival rate. In this study, we aimed to identify the expression of GTSE1 and its correlation with cisplatin resistance in gastric cancer cells.
  
  
  METHODS
  Methylation profiling was carried out in tissue samples from gastric cancer patients before undergoing neoadjuvent therapy using docetaxel, cisplatin and 5FU (DCX) and in gastric cancer cell lines. The correlation between GTSE1 expression and methylation in gastric cancer cells was determined by RT-PCR and MSP respectively. GTSE1 expression was knocked-down using shRNA's and its effects on cisplatin cytotoxicity and cell survival were detected by MTS, proliferation and clonogenic survival assays. Additionally, the effect of GTSE1 knock down in drug induced apoptosis was determined by western blotting and apoptosis assays.
  
  
  RESULTS
  GTSE1 exhibited a differential methylation index in gastric cancer patients and in cell lines that correlated with DCX treatment response and cisplatin sensitivity, respectively. In-vitro, GTSE1 expression showed a direct correlation with hypomethylation. Interestingly, Cisplatin treatment induced a dose dependent up regulation as well as nuclear translocation of GTSE1 expression in gastric cancer cells. Knock down of GTSE1 enhanced cisplatin cytotoxity and led to a significant reduction in cell proliferation and clonogenic survival. Also, loss of GTSE1 expression caused a significant increase in P53 mediated apoptosis in cisplatin treated cells.
  
  
  CONCLUSIONS
  Our study identifies GTSE1 as a biomarker for cisplatin resistance in gastric cancer cells. This study also suggests the repressive role of GTSE1 in cisplatin induced apoptosis and signifies its potential utility as a therapeutic target for better clinical management of gastric cancer patients.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. csivv@nus.edu.sg.
authors.forename: Vinod Vijay
authors.initials: VV
authors.lastname: Subhash
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. tan_shi_hui@nuhs.edu.sg.
authors.forename: Shi Hui
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. xa_vel927@hotmail.com.
authors.forename: Woei Loon
authors.initials: WL
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. yeomeishi@gmail.com.
authors.forename: Mei Shi
authors.initials: MS
authors.lastname: Yeo
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. matchxie@hotmail.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. wf_ying@hotmail.com.
authors.forename: Foong Ying
authors.initials: FY
authors.lastname: Wong
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. Ying_Kiat_Zee@nuhs.edu.sg.
authors.forename: Zee Ying
authors.initials: ZY
authors.lastname: Kiat
authors.affiliation: Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. Robert_lim@nuhs.edu.sg.
authors.forename: Robert
authors.initials: R
authors.lastname: Lim
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. Wei_Peng_YONG@nuhs.edu.sg.|Department of Haematology-Oncology, National University Hospital of Singapore, Singapore, Singapore. Wei_Peng_YONG@nuhs.edu.sg.
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C115080:GTSE1 protein, human; D008869:Microtubule-Associated Proteins; D002945:Cisplatin