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NOS2 enhances KRAS‐induced lung carcinogenesis, inflammation and microRNA‐21 expression
Author(s) -
Okayama Hirokazu,
Saito Motonobu,
Oue Naohide,
Weiss Jonathan M.,
Stauffer Jimmy,
Takenoshita Seiichi,
Wiltrout Robert H.,
Hussain S. Perwez,
Harris Curtis C.
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27644
Subject(s) - kras , carcinogenesis , cancer research , biology , lung cancer , inflammation , cell growth , microrna , downregulation and upregulation , cancer , medicine , pathology , immunology , colorectal cancer , biochemistry , genetics , gene
Mutant KRAS in lung cancers induces molecular pathways that regulate cellular proliferation, survival and inflammation, which enhance tumorigenesis. Inducible nitric oxide synthase (NOS2) upregulation and sustained nitric oxide generation are induced during the inflammatory response and correlate positively with lung tumorigenesis. To explore the mechanistic contribution of NOS2 to KRAS‐induced lung tumorigenesis and inflammation, we used a genetic strategy of crossing NOS2 knockout ( NOS2KO ) C57BL6 inbred mice with a KRAS G12D ‐driven mouse lung cancer model. KRAS G12D ;NOS2KO mice exhibited delayed lung tumorigenesis and a longer overall survival time compared to that of KRAS G12D ;NOS2WT (wild‐type) controls. Correspondingly, tumors in KRAS G12D ;NOS2KO mice had reduced tumor cell proliferation in adenomas and carcinomas. NOS2 deficiency also led to markedly suppressed inflammatory response by attenuation of macrophage recruitment into alveoli and within tumor foci. In contrast, FOXP3+ regulatory T cells were increased in tumors from KRAS G12D ;NOS2KO mice. We further analyzed the expression of microRNA‐21 (miR‐21), an oncogenic noncoding RNA involved in oncogenic Ras signaling, by quantitative reverse‐transcription polymerase chain reaction and in situ hybridization. Lung carcinomas dissected from KRAS G12D ;NOS2KO mice showed a significantly reduced miR‐21 expression along with decreased tumor cell proliferation, suggesting that NOS2 deficiency could attenuate RAS signaling pathways that transactivate miR‐21 expression. Therefore, deletion of NOS2 decreases lung tumor growth as well as inflammatory responses initiated by oncogenic KRAS, suggesting that both KRAS and NOS2 cooperate in driving lung tumorigenesis and inflammation. Inhibition of NOS2 may have a therapeutic value in lung cancers with oncogenic KRAS mutations.