title: WT1 enhances proliferation and impedes apoptosis in KRAS mutant NSCLC via targeting cMyc.
abstract: BACKGROUND
  A novel link between oncogenic KRAS signalling and WT1 was recently identified. We sought to investigate the role of WT1 and KRAS in proliferation and apoptosis.
  
  
  METHODS
  KRAS mutations and WT1 (cMyc) expression were detected using Sanger sequencing and real-time PCR in 77 patients with non-small cell lung cancer (NSCLC). Overexpression and knockdown of WT1 were generated with plasmid and siRNA via transient transfection technology in H1299 and H1568 cells. MTT assay for detection of cell proliferation, and TUNEL assay and proteomic profiler assay for apoptosis evaluation were carried out. Dual luciferase reporter assay and ChIP-PCR were performed to validate the effect of WT1 on the cMyc promoter.
  
  
  RESULTS
  KRAS mutations showed a negative impact on overall survival (OS). High expressions of WT1 and cMyc were associated with poor OS in KRAS mutant subgroup. The potential mechanisms that WT1 promotes proliferation and impedes apoptosis through affecting multiple apoptosis-related regulators in KRAS mutant NSCLC cells were identified. WT1 could activate cMyc promoter directly in KRAS mutant cells.
  
  
  CONCLUSIONS
  The results suggest that WT1 and c-MYC expression is important for survival in KRAS mutant tumors as opposed to KRAS wild-type tumors. For treatment of KRAS mutant NSCLC, targeting WT1 and cMyc may provide alternative therapeutic strategies.
authors.affiliation: Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wu
authors.forename: Sihan
authors.initials: S
authors.lastname: Wang
authors.forename: Caihua
authors.initials: C
authors.lastname: Xu
authors.forename: Andreas
authors.initials: A
authors.lastname: Tyler
authors.forename: Xingru
authors.initials: X
authors.lastname: Li
authors.forename: Charlotta
authors.initials: C
authors.lastname: Andersson
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oji
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Yijiang
authors.initials: Y
authors.lastname: Chen
authors.forename: Aihong
authors.initials: A
authors.lastname: Li
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D025721:WT1 Proteins; C583751:WT1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins