Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar.
Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt.
Cell Commun Signal. 2017 Nov 9;15(1):45. doi: 10.1186/s12964-017-0200-3.
We have previously validated three novel CD44-downstream positively regulated transcriptional targets, including Cortactin, Survivin and TGF-β2, and further characterized the players underlying their separate signaling pathways. In the present study, we identified CD146 as a potential novel target, negatively regulated by CD44. While the exact function of CD146 in breast cancer (BC) is not completely understood, substantial evidence from our work and others support the hypothesis that CD146 is a suppressor of breast tumor progression.
Therefore, using molecular and pharmacological approaches both in vitro and in breast tissues of human samples, the present study validated CD146 as a novel target of CD44-signaling suppressed during BC progression.
Our results revealed that CD44 activation could cause a substantial decrease of CD146 expression with an equally notable converse effect upon CD44-siRNA inhibition. More interestingly, activation of CD44 decreased cellular CD146 and increased soluble CD146 through CD44-dependent activation of MMP.
Here, we provide a possible mechanism by which CD146 suppresses BC progression as a target of CD44-downstream signaling, regulating neovascularization and cancer cell motility.
我们之前已经验证了三个新的 CD44 下游正向调控的转录靶标，包括 Cortactin、Survivin 和 TGF-β2，并进一步描述了它们各自信号通路背后的作用因子。在本研究中，我们发现 CD146 是一个潜在的新靶点，受 CD44 负调控。虽然 CD146 在乳腺癌（BC）中的确切功能尚未完全了解，但我们和其他人的大量证据支持 CD146 是乳腺癌进展的抑制因子这一假说。
因此，本研究通过体外和人乳腺组织样本的分子和药理学方法，验证了 CD146 是 CD44 信号通路在 BC 进展过程中被抑制的一个新靶标。
我们的结果表明，CD44 的激活会导致 CD146 表达的大量减少，而当 CD44-siRNA 抑制时，CD146 的表达则会出现显著的反向增加。更有趣的是，CD44 的激活通过 MMP 的 CD44 依赖性激活降低细胞表面 CD146 的表达，同时增加可溶性 CD146。
在这里，我们提供了一种可能的机制，即 CD146 作为 CD44 下游信号的靶标，通过调节血管生成和癌细胞迁移来抑制 BC 的进展。
