Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis.
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.
Okudela
Koji
K
Department of Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-Ku, 236-0004 Yokohama, Japan.
Yazawa
Takuya
T
Woo
Tetsukan
T
Sakaeda
Masashi
M
Ishii
Jun
J
Mitsui
Hideaki
H
Shimoyamada
Hiroaki
H
Sato
Hanako
H
Tajiri
Michihiko
M
Ogawa
Nobuo
N
Masuda
Munetaka
M
Takahashi
Takashi
T
Sugimura
Haruhiko
H
Kitamura
Hitoshi
H
D022981:Allelic Imbalance; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D015533:Transcriptional Activation; D018631:ras Proteins / Q000378:metabolism*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins