Inhibitory Roles of Signal Transducer and Activator of Transcription 3 in Antitumor Immunity during Carcinogen-Induced Lung Tumorigenesis

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 a...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2012-06, Vol.72 (12), p.2990-2999
Main Authors: IHARA, Shoichi, KIDA, Hiroshi, INOUE, Ruriko, HASEGAWA, Kana, GOYA, Sho, TAKAHASHI, Ryo, MINAMI, Toshiyuki, TSUJINO, Kazuyuki, SUZUKI, Mayumi, KOHMO, Satoshi, INOUE, Koji, NAGATOMO, Izumi, ARASE, Hisashi, TAKEDA, Yoshito, KIJIMA, Takashi, MIZUGUCHI, Kenji, TACHIBANA, Isao, KUMANOGOH, Atsushi, TRIPATHI, Lokesh P, CHEN, Yi-An, KIMURA, Tetsuya, YOSHIDA, Mitsuhiro, KASHIWA, Yozo, HIRATA, Haruhiko, FUKAMIZU, Reiko
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Apoptosis
Biological and medical sciences
Carcinogens
Carcinoma, Non-Small-Cell Lung - chemically induced
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - immunology
Carcinoma, Non-Small-Cell Lung - metabolism
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
Culture Media, Conditioned
Cytokines - biosynthesis
HLA Antigens - biosynthesis
Humans
Killer Cells, Natural - immunology
Lung Neoplasms - chemically induced
Lung Neoplasms - immunology
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Medical sciences
Mice
Mice, Knockout
Pharmacology. Drug treatments
RNA Interference
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Small Interfering
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
Tumors
Urethane
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Summary: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(Δ/Δ)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Δ/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 Stat3(Δ/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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-11-4062