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 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.
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Japan.
Shoichi
S
Ihara
Hiroshi
H
Kida
Hisashi
H
Arase
Lokesh P
LP
Tripathi
Yi-An
YA
Chen
Tetsuya
T
Kimura
Mitsuhiro
M
Yoshida
Yozo
Y
Kashiwa
Haruhiko
H
Hirata
Reiko
R
Fukamizu
Ruriko
R
Inoue
Kana
K
Hasegawa
Sho
S
Goya
Ryo
R
Takahashi
Toshiyuki
T
Minami
Kazuyuki
K
Tsujino
Mayumi
M
Suzuki
Satoshi
S
Kohmo
Koji
K
Inoue
Izumi
I
Nagatomo
Yoshito
Y
Takeda
Takashi
T
Kijima
Kenji
K
Mizuguchi
Isao
I
Tachibana
Atsushi
A
Kumanogoh
D000818:Animals; D017209:Apoptosis; D002273:Carcinogens; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000096:biosynthesis; D006680:HLA Antigens / Q000096:biosynthesis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014520:Urethane
D002273:Carcinogens; D017077:Culture Media, Conditioned; D016207:Cytokines; D006680:HLA Antigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014520:Urethane