Inhibitory role of Gas6 in intestinal tumorigenesis
| Autor: | Hiroshi Seno, Mayumi Kawada, Yuto Kimura, Yoshiharu Sakai, Tsutomu Chiba, Keitaro Kanda, Takuto Yoshioka, Masato Nakatsuji, Kenji Kawada, Reiko Akitake-Kawano, Yuki Nakanishi |
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| Rok vydání: | 2013 |
| Předmět: |
Lipopolysaccharides
Male Cancer Research Stromal cell Lipopolysaccharide Azoxymethane Suppressor of Cytokine Signaling Proteins Biology medicine.disease_cause Monocytes chemistry.chemical_compound HT29 Cells Mice Immune system Suppressor of Cytokine Signaling 1 Protein Bone Marrow medicine Animals Humans RNA Messenger Aged Bone Marrow Transplantation Cell Proliferation Aged 80 and over Mice Knockout GAS6 Dextran Sulfate NF-kappa B Cancer General Medicine Middle Aged medicine.disease Colitis Prognosis Molecular biology Recombinant Proteins Gene Expression Regulation Neoplastic Mice Inbred C57BL Cell Transformation Neoplastic chemistry Disease Progression Intercellular Signaling Peptides and Proteins Female Carcinogenesis Colorectal Neoplasms |
| Zdroj: | Carcinogenesis. 34(7) |
| ISSN: | 1460-2180 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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