Elevated expression of Cyr61 enhances peritoneal dissemination of gastric cancer cells through integrin alpha2beta1.
Elevated expression of Cyr61 enhances peritoneal dissemination of gastric cancer cells through integrin alpha2beta1.
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发表时间：
2007
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通讯作者：
Ming-Tsan Lin;Cheng‐Chi Chang;Been-Ren Lin;Hsin-Yu Yang;C. Chu;Ming-Hsun Wu;M. Kuo
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作者：
Ming-Tsan Lin;Cheng‐Chi Chang;Been-Ren Lin;Hsin-Yu Yang;C. Chu;Ming-Hsun Wu;M. Kuo
富含半胱氨酸61（Cyr61/CCN 1）参与人胃癌的发生和发展。尽管如此，Cyr61的腹膜传播的这种癌症的作用还没有完全的特点。我们使用脂质体介导的转染，建立Cyr 61，或反义Cyr 61，表达载体到胃癌AGS或MKN 45细胞系。通过体外和离体癌细胞粘附测定来测试转染子。此外，功能性整合素荧光激活细胞分选试验，逆转录-PCR，和AP-1报告分析进行调查Cyr61的潜在信号通路。结果表明，Cyr61稳定转染到AGS细胞系中强烈增强了其粘附能力。Cyr61在AGS细胞内的过表达显著增加了整合素α（2）β（1）的功能表达。针对整合素α（2）β（1）的功能中和抗体有效地抑制了Cyr61介导的AGS细胞与腹膜组织的粘附增强。整合素α 2基因的启动子分析进一步揭示了AP-1通路在表达Cyr61的AGS细胞中被明显激活。动物研究表明，注射Cyr61过表达的AGS细胞的小鼠，其腹膜接种结节数量更多，存活率低于Neo对照细胞系，当用整合素α（2）β（1）的功能性阻断抗体处理这些细胞时，它们能够引起腹膜播散的下降。这些数据表明，Cyr61可能通过AP-1依赖性途径上调功能性整合素α（2）β（1），从而促进肿瘤细胞粘附能力，从而促进胃癌的腹膜播散。
Cysteine-rich 61 (Cyr61/CCN1) is involved in human gastric cancer development and progression. Nonetheless, the role of Cyr61 as regards peritoneal dissemination of such cancers has not yet been completely characterized. We used liposome-mediated transfection to establish Cyr61, or antisense Cyr61, expression vectors into gastric cancer AGS or MKN45 cell lines. Transfectants were tested by means of a cancer-cell adhesion assay in vitro and ex vivo. Furthermore, a functional integrin fluorescence-activated cell sorting assay, reverse transcription-PCR, and an AP-1 reporter assay were performed to investigate the potential signaling pathway of Cyr61. It was shown that stable transfection of Cyr61 into the AGS cell line strongly enhanced its adhesion ability. The overexpression of Cyr61 within AGS cells significantly increased the functional expression of integrin alpha(2)beta(1). Function-neutralizing antibody to integrin alpha(2)beta(1) effectively suppressed the Cyr61-mediated enhanced adhesion of AGS cells to peritoneal tissue. Promoter assays of integrin alpha2 gene further revealed that the AP-1 pathway was evidently activated within Cyr61-expressing AGS cells. Animal studies have revealed that mice injected with Cyr61-overexpressed AGS cells featured a greater number of peritoneal seeding nodules and a lower survival rate than the Neo control cell lines, and when such cells were treated with functional blocking antibody to integrin alpha(2)beta(1), they were able to elicit a decline in the peritoneal dissemination. The data suggest that Cyr61 may contribute to the peritoneal dissemination of gastric cancer by promoting tumor-cell adhesion ability through the up-regulation of the functional integrin alpha(2)beta(1) via an AP-1-dependent pathway.