1. Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis
- Author
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Kana Hasegawa, Takashi Kijima, Ruriko Inoue, Kenji Mizuguchi, Koji Inoue, Hiroshi Kida, Ryo Takahashi, Yi-An Chen, Hisashi Arase, Lokesh P. Tripathi, Reiko Fukamizu, Mayumi Suzuki, Yoshito Takeda, Shoichi Ihara, Yozo Kashiwa, Sho Goya, Haruhiko Hirata, Kazuyuki Tsujino, Satoshi Kohmo, Atsushi Kumanogoh, Izumi Nagatomo, Toshiyuki Minami, Isao Tachibana, Mitsuhiro Yoshida, and Tetsuya Kimura
- Subjects
STAT3 Transcription Factor ,Cancer Research ,Chemokine ,Lung Neoplasms ,Cell ,Apoptosis ,Biology ,medicine.disease_cause ,Urethane ,Proinflammatory cytokine ,Mice ,HLA Antigens ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Animals ,Humans ,RNA, Messenger ,RNA, Small Interfering ,STAT3 ,Cell Proliferation ,Mice, Knockout ,Cell growth ,Monocyte ,Killer Cells, Natural ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,Culture Media, Conditioned ,Immunology ,Cancer research ,biology.protein ,STAT protein ,Carcinogens ,Cytokines ,RNA Interference ,Carcinogenesis - Abstract
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 (Stat3Δ/Δ) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3Δ/Δ 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 Stat3Δ/Δ 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. ©2012 AACR.
- Published
- 2012