Journal
CANCER RESEARCH
Volume 72, Issue 12, Pages 2990-2999Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-4062
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Funding
- KAKENHI [20890116]
- Osaka Foundation for Promotion of Clinical Immunology
- New Energy and Industrial Technology Development Organization (NEDO) of Japan
- Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation
- Funding Program for Next Generation World-Leading Researchers (NEXT Program)
- Special Coordination Funds for Promoting Science and Technology
- Grants-in-Aid for Scientific Research [23659223, 24659223, 23390112, 24115005, 20890116] Funding Source: KAKEN
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Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3(Delta/Delta)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Delta/Delta) mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3(Delta/Delta) tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis. Cancer Res; 72(12); 2990-9. (C)2012 AACR.
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