Suppression of E-cadherin function drives the early stages of Ras-induced squamous cell carcinoma through upregulation of FAK and Src.
Suppression of E-cadherin function drives the early stages of Ras-induced squamous cell carcinoma through upregulation of FAK and Src.
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DOI：
10.1038/jid.2011.188
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发表时间：
2011-11
影响因子：
6.5
通讯作者：
Garlick, Jonathan A.
中科院分区：
文献类型：
--
作者：
Alt-Holland, Addy;Sowalsky, Adam G.;Szwec-Levin, Yonit;Shamis, Yulia;Hatch, Harold;Feig, Larry A.;Garlick, Jonathan A.
上皮癌发生的晚期阶段涉及细胞间粘附的丧失，但仍不清楚调节细胞-细胞和细胞-基质粘附改变的蛋白质如何被解除调节以促进癌症发展的早期阶段。为了解决这一问题，使用模拟鳞状细胞癌（SCC）初期阶段的三维人体组织模型来研究E-钙粘蛋白抑制如何促进Ras表达的人角质形成细胞中的肿瘤进展。我们发现，E-钙粘蛋白抑制引发局部粘附激酶（FAK）的mRNA和蛋白质表达水平升高，并增加FAK和Src活性高于Ras表达E-钙粘蛋白的角质形成细胞中的水平。sh-RNA介导的FAK和Src的耗竭通过增加其在膜中的稳定性来恢复E-cadherin的表达水平，并阻断肿瘤细胞在组织中的侵袭。将这些组织表面移植到小鼠体内，导致肿瘤表型逆转为低级别肿瘤岛，而对照组织表现为侵袭性高级别SCC。这些研究结果表明，E-钙粘蛋白抑制的肿瘤促进作用，在SCC发展中的常见事件，是加剧了由升高的FAK和Src活动诱导的增强E-钙粘蛋白降解。此外，他们暗示，在具有肿瘤潜能的人上皮细胞中靶向FAK或Src可能抑制SCC的早期阶段。
Advanced stages of epithelial carcinogenesis involve the loss of intercellular adhesion, but it remains unclear how proteins that regulate alterations in cell-cell and cell-matrix adhesion are deregulated to promote the early stages of cancer development. To address this, a three-dimensional human tissue model that mimics the incipient stages of Squamous Cell Carcinoma (SCC) was used to study how E-cadherin suppression promotes tumor progression in Ras-expressing human keratinocytes. We found that E-cadherin suppression triggered elevated mRNA and protein expression levels of Focal Adhesion Kinase (FAK), and increased FAK and Src activities above the level seen in Ras-expressing E-cadherin-competent keratinocytes. sh-RNA-mediated depletion of FAK and Src restored E-cadherin expression levels by increasing its stability in the membrane, and blocked tumor cell invasion in tissues. Surface transplantation of these tissues to mice resulted in reversion of the tumor phenotype to low-grade tumor islands in contrast to control tissues that manifested an aggressive, high-grade SCC. These findings suggest that the tumor-promoting effect of E-cadherin suppression, a common event in SCC development, is exacerbated by enhanced E-cadherin degradation induced by elevated FAK and Src activities. Furthermore, they imply that targeting FAK or Src in human epithelial cells with neoplastic potential may inhibit the early stages of SCC.
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通讯作者：
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