アクティブボード・２０１６年３月
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研究発表を行った学会；
・第13回日韓合同血管生物医学会学術総会
　２０１５年１０月１５日〜１７日（釜山、韓国）

タイトル；AKAP12/SSeCKS regulates lung metastasis through controlling pre-metastatic niche formation.
発表者；村松 　昌　氏
　　　（熊本大学　生命資源研究・支援センター　表現型解析分野）
要旨；
There are growing appreciations for the formation of the pre-metastatic niches, and the role of the senescence-associated secretory phenotype (SASP) in promoting metastasis progression through the upregulation of inflammatory mediators at distal organs. However, little is known about the pathways controlling the pre-metastatic niche formation and metastasis-promoting SASP. Knockout mice for the AKAP12/SSeCKS metastasis suppressor (Akap12-/-) exhibit significantly more lung metastasis colonies compared to wild type hosts following i.v. injection of melanoma cells. Enhanced lung metastasis in Akap12-/- mice correlated with increased tumor cell adhesion through increased E-selectin expression. Knockdown of AKAP12 in endothelial cells was attenuated endogenous E-selectin and following the tumor cell adhesion. Additionally, an activated calcineurin-NFAT pathway is involved in mechanisms underlying angiogenesis in the pre-metastatic niche at lung via increased NFAT target genes such as Angiopoietin-2 and E-selectin. Since AKAP12 has four calmodulin-binding sites, it may regulate calcineurin-NFAT pathway results in increased E-selectin expression. Moreover, pre-incubation of endothelial cells with conditioned media from lung fibroblasts from Akap12-/- mice induced E-selectin and tumor cell adhesion, correlated with the upregulation of Vegf, Heregulin and Syntaxin-2. Co-injection of melanoma cells with Akap12-/--lung fibroblasts into wild type hosts resulted in increased lung metastasis formation. Their fibroblasts exhibited increased Rb-dependent premature senescence and SASP factor secretion caused by hyper-activated PKCα and ε, and Src-mediated STAT3 signaling, which correlated with increased levels of p16Ink4a, p21Cip1 and senescence-associated β-galactosidase. Taken together, our data strongly suggest that AKAP12 normally suppresses the formation of the pre-metastatic niches and metastasis-promoting SASP by attenuating NFAT, PKC and Src-mediated STAT3 pathways in microenvironment. These data would support the use of blocking of these pathways lead to therapeutically prevent the metastasis by targeting pre-metastatic niche formation.