NOS2 enhances KRAS‐induced lung carcinogenesis, inflammation and microRNA‐21 expression1. Issue 1 (13th June 2012)

• Record Type: Journal Article
• Authors: Okayama, Hirokazu; Saito, Motonobu; Oue, Naohide; Weiss, Jonathan M.; Stauffer, Jimmy; Takenoshita, Seiichi; Wiltrout, Robert H.; Hussain, S. Perwez; Harris, Curtis C.
• Is Part Of: International journal of cancer. Volume 132:Issue 1(2013:Jan. 01)
• Page Start: 9
• Page End: 18
• Publication Date: 2012-06-13
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.27644
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Mutant <italic>KRAS</italic> 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 <italic>NOS2</italic> knockout (<italic>NOS2KO</italic>) C57BL6 inbred mice with a <italic>KRAS</italic><sup><italic>G12D</italic></sup>‐driven mouse lung cancer model. <italic>KRAS<sup>G12D</sup>;NOS2KO</italic> mice exhibited delayed lung tumorigenesis and a longer overall survival time compared to that of <italic>KRAS<sup>G12D</sup>;NOS2WT</italic> (wild‐type) controls. Correspondingly, tumors in <italic>KRAS<sup>G12D</sup>;NOS2KO</italic> 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 <italic>KRAS<sup>G12D</sup>;NOS2KO</italic> 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 <italic>in situ</italic> hybridization. Lung carcinomas dissected from <italic>KRAS<sup>G12D</sup>;NOS2KO</italic> 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.</p> </abstract>