|Title:||Inhibitory role of Gas6 in intestinal tumorigenesis.|
|Author's alias:||秋武, 玲子|
|Publisher:||Oxford University Press|
|Abstract:||Growth 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.|
|Rights:||This 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: http://carcin.oxfordjournals.org/content/34/7/1567|
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|Appears in Collections:||Journal Articles |
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