RRC ID 62190
Author Okudela K, Yazawa T, Woo T, Sakaeda M, Ishii J, Mitsui H, Shimoyamada H, Sato H, Tajiri M, Ogawa N, Masuda M, Takahashi T, Sugimura H, Kitamura H.
Title Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis.
Journal Am J Pathol
Abstract Our preliminary studies revealed that oncogenic KRAS (KRAS/V12) dramatically suppressed the growth of immortalized airway epithelial cells (NHBE-T, with viral antigen-inactivated p53 and RB proteins). This process appeared to be a novel event, different from the so-called premature senescence that is induced by either p53 or RB, suggesting the existence of a novel tumor suppressor that functions downstream of oncogenic KRAS. After a comprehensive search for genes whose expression levels were modulated by KRAS/V12, we focused on DUSP6, a pivotal negative feedback regulator of the RAS-ERK pathway. A dominant-negative DUSP6 mutant, however, failed to rescue KRAS/V12-induced growth suppression, but conferred a stronger anchorage-independent growth activity to the surviving subpopulation of cells generated from KRAS/V12-transduced NHBE-T. DUSP6 expression levels were found to be weaker in most lung cancer cell lines than in NHBE-T, and DUSP6 restoration suppressed cellular growth. In primary lung cancers, DUSP6 expression levels decreased as both growth activity and histological grade of the tumor increased. Loss of heterozygosity of the DUSP6 locus was found in 17.7% of cases and was associated with reduced expression levels. These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. We have here identified an important factor involved in carcinogenesis through a comprehensive search for downstream targets of oncogenic KRAS.
Volume 175(2)
Pages 867-81
Published 2009-8-1
DOI 10.2353/ajpath.2009.080489
PII S0002-9440(10)60598-6
PMID 19608870
PMC PMC2716981
MeSH Allelic Imbalance Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic / genetics* Cell Transformation, Neoplastic / pathology CpG Islands DNA Methylation Down-Regulation Dual Specificity Phosphatase 6 / genetics* Gene Expression Regulation, Neoplastic* Humans Lung Neoplasms / genetics* Lung Neoplasms / pathology Mutation Promoter Regions, Genetic Protein Biosynthesis / genetics Proto-Oncogene Proteins / metabolism* Proto-Oncogene Proteins p21(ras) Transcriptional Activation ras Proteins / metabolism*
IF 3.491
Human and Animal Cells LC-2/ad(RCB0440) Lu-134-A(RCB0466) Lu-140(RCB0470)