c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-β signaling in diffuse-type gastric carcinoma
c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-β signaling in diffuse-type gastric carcinoma
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DOI：
10.1111/j.1349-7006.2009.01248.x
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发表时间：
2009-10-01
期刊：
影响因子：
5.7
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Kiyono, Kunihiko;Suzuki, Hiroshi I.;Miyazono, Kohei
c-Ski最初被鉴定为原癌基因产物，通过与Smad2、Smad3、Smad4相互作用，是转化生长因子(TGF)- β家族信号传导的重要负调控因子。c-Ski在包括胃癌在内的一些癌症中有高表达。我们之前的研究表明，在弥漫性胃癌模型中，显性阴性tgf - β II型受体破坏tgf - β信号通路，通过降低抗血管生成因子血小板反应蛋白(TSP)-1的表达，诱导肿瘤血管生成，从而加速肿瘤生长。在这里，我们检测了c-Ski在人弥漫性胃癌OCUM-2MLN细胞中的功能。c-Ski过表达抑制OCUM-2MLN细胞中tgf - β信号传导。有趣的是，c- ski过表达导致BALB/c nu/nu雌性小鼠（6周龄）皮下异种移植物生长广泛加速。与表达显性阴性tgf - β II型受体的肿瘤类似，组织化学研究显示，与对照肿瘤相比，表达c-Ski的异种移植肿瘤纤维化较少，血管生成增加。体外c-Ski可减弱tgf - β对TSP-1 mRNA的诱导作用，体内表达c-Ski的肿瘤中TSP-1 mRNA的表达降低。这些结果表明，c-Ski过表达通过诱导血管生成促进弥漫性胃癌的生长。（癌症科学2009；100:1809-1816）。
c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-beta signaling by dominant-negative TGF-beta type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-beta type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-beta was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis. (Cancer Sci 2009; 100: 1809-1816).