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dc.contributor.authorAkitake-Kawano, Reikoen
dc.contributor.authorSeno, Hiroshien
dc.contributor.authorNakatsuji, Masatoen
dc.contributor.authorKimura, Yutoen
dc.contributor.authorNakanishi, Yukien
dc.contributor.authorYoshioka, Takutoen
dc.contributor.authorKanda, Keitaroen
dc.contributor.authorKawada, Mayumien
dc.contributor.authorKawada, Kenjien
dc.contributor.authorSakai, Yoshiharuen
dc.contributor.authorChiba, Tsutomuen
dc.contributor.alternative秋武, 玲子ja
dc.contributor.alternative妹尾, 浩ja
dc.description.abstractGrowth arrest-specific gene (Gas) 6 is a γ-carboxyglutamic acid domain-containing protein, which shares 43% amino acid identity with protein S. Gas6 has been shown to enhance cancer cell proliferation in vitro. On the other hand, recent studies have demonstrated that Gas6 inhibits toll-like receptor-mediated immune reactions. Immune reactions are known to affect intestinal tumorigenesis. In this study, we investigated how Gas6 contributes to tumorigenesis in the intestine. Administration of recombinant Gas6 weakly, but significantly, enhanced proliferation of intestinal cancer cells (SW480 and HT29), whereas it suppressed the inflammatory responses of Lipopolysaccharide (LPS)-stimulated monocytes (THP-1). Compared with Gas6(+/+) mice, Gas6(-/-) mice exhibited enhanced azoxymethane/dextran sulfate sodium (DSS)-induced tumorigenesis and had a shorter survival. Gas6(-/-) mice also exhibited more severe DSS-induced colitis. DSS-treated Gas6(-/-) mice showed attenuated Socs1/3 messenger RNA expression and enhanced nuclear factor-kappaB activation in the colonic stroma, suggesting that the target of Gas6 is stromal cells. Bone marrow transplantation experiments indicated that both epithelial cells and bone marrow-derived cells are Gas6 sources. Furthermore, the number of intestinal tumors in Apc(Min) Gas6(-/-) mice was higher than that in Apc(Min) Gas6(+/+) mice, resulting in shorter survival. In a group of 62 patients with advanced colorectal cancer, Gas6 immunoreactivity in cancer tissues was positively correlated with prognosis. Thus, we revealed a unique in vivo inhibitory role of Gas6 during the progression of intestinal tumors associated with suppression of stromal immune reactions. These results suggest a novel therapeutic approach for colorectal cancer patients by regulation of stromal immune responses.en
dc.publisherOxford University Pressen
dc.rightsThis is a pre-copyedited, author-produced PDF of an article accepted for publication in "Carcinogenesis" following peer review. The version of record "Reiko Akitake-Kawano, Hiroshi Seno, Masato Nakatsuji, Yuto Kimura, Yuki Nakanishi, Takuto Yoshioka, Keitaro Kanda, Mayumi Kawada, Kenji Kawada, Yoshiharu Sakai, and Tsutomu Chiba; Inhibitory role of Gas6 in intestinal tumorigenesis; Carcinogenesis (2013) 34 (7): 1567-1574 first published online February 20, 2013 doi:10.1093/carcin/bgt069" is available online at:
dc.rightsThis is not the published version. Please cite only the published version.en
dc.subject.meshAged, 80 and overen
dc.subject.meshAzoxymethane/adverse effectsen
dc.subject.meshBone Marrow/metabolismen
dc.subject.meshBone Marrow Transplantation/methodsen
dc.subject.meshCell Proliferation/drug effectsen
dc.subject.meshCell Transformation, Neoplasticen
dc.subject.meshColitis/chemically induceden
dc.subject.meshColorectal Neoplasms/metabolismen
dc.subject.meshColorectal Neoplasms/pathologyen
dc.subject.meshDextran Sulfate/pharmacologyen
dc.subject.meshDisease Progressionen
dc.subject.meshGene Expression Regulation, Neoplasticen
dc.subject.meshHT29 Cellsen
dc.subject.meshIntercellular Signaling Peptides and Proteins/administration & dosageen
dc.subject.meshIntercellular Signaling Peptides and Proteins/metabolismen
dc.subject.meshIntercellular Signaling Peptides and Proteins/pharmacologyen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Knockouten
dc.subject.meshMiddle Ageden
dc.subject.meshMonocytes/drug effectsen
dc.subject.meshNF-kappa B/geneticsen
dc.subject.meshNF-kappa B/metabolismen
dc.subject.meshRNA, Messenger/geneticsen
dc.subject.meshRNA, Messenger/metabolismen
dc.subject.meshRecombinant Proteins/administration & dosageen
dc.subject.meshRecombinant Proteins/pharmacologyen
dc.subject.meshSuppressor of Cytokine Signaling Proteins/geneticsen
dc.subject.meshSuppressor of Cytokine Signaling Proteins/metabolismen
dc.titleInhibitory role of Gas6 in intestinal tumorigenesis.en
dc.typejournal article-
dc.type.niitypeJournal Article-
dcterms.accessRightsopen access-
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