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.