The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1
The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1
复制标题
DOI：
10.1158/0008-5472.can-09-3281
复制
发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Laird, Dale W.
中科院分区：
文献类型：
--
作者：
Langlois, Stephanie;Cowan, Kyle N.;Laird, Dale W.
已知 Connexin43 (Cx43) 具有肿瘤抑制作用，但其潜在机制仍知之甚少。在角质形成细胞中，我们之前表明 Cx43 的 COOH 末端结构域直接与肿瘤抑制因子 Cav-1 相互作用。我们现在表明，Cx43 减少的大鼠表皮角质形成细胞 (REK) 呈现出上皮间质转化的特征，并且比其对照对应物更具侵袭性，而 Cx43 的过表达抑制了 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 和表皮生长因子 (EGF) 诱导的侵袭特性。 Carbenoxolone 没有改变 Cx43 对 TPA 和 EGF 诱导的细胞侵袭的抑制作用，表明涉及间隙连接细胞间通讯独立机制。有趣的是，经过 TPA 和 EGF 治疗后，发现 Cx43 与 Cav-1 的关联性降低。因此，在人表皮鳞状细胞癌细胞以及人角质形成细胞肿瘤切片中，Cx43 与 Cav-1 的共定位减弱，表明 Cx43/Cav-1 相互作用对角质形成细胞转化发挥保护作用。与过度表达 Cx43-GFP 的细胞相反，在过度表达 GFP 标记的 Cx43 截短突变体 (Delta 244-GFP) 的大鼠表皮角质形成细胞中以及在过度表达 Cx43-GFP 但在 Cav-1 中减少的细胞中，以及在过度表达 Cx43-GFP 但在 Cav-1 中减少的细胞中，可以诱导侵袭，而我们之前表明该突变体不会与 Cav-1 相互作用。我们的数据表明，Cx43 在角质形成细胞中具有肿瘤抑制特性，并提供了第一个证据，证明 Cx43/Cav-1 相互作用在角质形成细胞转化过程以及人类角质形成细胞肿瘤中发生改变，并且这种关联可能在 Cx43 介导的肿瘤抑制中发挥作用。癌症研究； (70) 10； 4222-32。 (C) 2010 AACR。
Connexin43 (Cx43) is known to have tumor-suppressive effects, but the underlying mechanisms are still poorly understood. In keratinocytes, we previously showed that the COOH-terminal domain of Cx43 directly interacts with the tumor suppressor Cav-1. We now show that rat epidermal keratinocytes (REK) that are reduced in Cx43 present features of epithelial-to-mesenchymal transition and are more invasive than their control counterparts, whereas overexpression of Cx43 inhibited the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)- and epidermal growth factor (EGF)-induced invasive properties. Carbenoxolone did not alter the inhibitory effect of Cx43 against TPA- and EGF-induced cell invasion, indicating the involvement of a gap junctional intercellular communication-independent mechanism. Interestingly, the association of Cx43 with Cav-1 was found to be reduced after TPA and EGF treatment. Accordingly, the colocalization of Cx43 with Cav-1 was diminished in cells from a human epidermal squamous cell carcinoma, as well as in sections from human keratinocyte tumors, suggesting that Cx43/Cav-1 interaction plays a protective role against keratinocyte transformation. As opposed to cells that overexpress Cx43-GFP, invasion could be induced in rat epidermal keratinocytes that overexpressed a GFP-tagged truncated mutant of Cx43 (Delta 244-GFP) that we previously showed not to interact with Cav-1, as well as in cells that overexpressed Cx43-GFP but were reduced in Cav-1. Our data show that Cx43 possesses tumor-suppressive properties in keratinocytes and provide the first evidence that the Cx43/Cav-1 interaction is altered in keratinocyte transformation processes, as well as in human keratinocyte tumors, and that this association might play a role in Cx43-mediated tumor suppression. Cancer Res; (70) 10; 4222-32. (C) 2010 AACR.