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WT1 Enhances Proliferation and Impedes Apoptosis in KRAS Mutant NSCLC via Targeting cMyc
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
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2015 (English)In: Cellular Physiology and Biochemistry, ISSN 1015-8987, E-ISSN 1421-9778, Vol. 35, no 2, 647-662 p.Article in journal (Refereed) Published
Abstract [en]

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 amd 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. Conclusion: 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.

Place, publisher, year, edition, pages
2015. Vol. 35, no 2, 647-662 p.
Keyword [en]
KRAS mutation, WT1, cMyc, NSCLC, Apoptosis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-100786DOI: 10.1159/000369726ISI: 000349032700019PubMedID: 25613309OAI: oai:DiVA.org:umu-100786DiVA: diva2:794388
Available from: 2015-03-11 Created: 2015-03-09 Last updated: 2017-12-04Bibliographically approved

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Wu, ChenWang, SihanTyler, AndreasLi, XingruAndersson, CharlottaLi, Aihong
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