Matrix rigidity regulates a switch between TGF-β1-induced apoptosis and epithelial-mesenchymal transition.
Matrix rigidity regulates a switch between TGF-β1-induced apoptosis and epithelial-mesenchymal transition.
复制标题
DOI：
10.1091/mbc.e11-06-0537
复制
发表时间：
2012-03
影响因子：
3.3
通讯作者：
Chen CS
中科院分区：
文献类型：
--
作者：
Leight JL;Wozniak MA;Chen S;Lynch ML;Chen CS
基质刚性调节两种上皮细胞系中TGF-β1诱导的细胞功能之间的转换在柔性聚丙烯酰胺凝胶上，TGF-β1诱导细胞凋亡，而在刚性凝胶上，细胞经历上皮-间充质转化（EMT）。顺应性凝胶降低了PI 3 K/Akt活性，这对于刚性凝胶上的细胞存活和EMT至关重要。转化生长因子-β（TGF-β）信号通路在癌症进展期间经常被错误调节。在肿瘤发生的早期阶段，TGF-β通过抑制增殖和诱导凋亡而充当肿瘤抑制因子。然而，随着疾病的进展，TGF-β转变为促进致瘤细胞功能，如上皮-间充质转化（EMT）和细胞运动性增加。细胞微环境的急剧变化也与肿瘤进展相关，包括组织硬度的增加。然而，尚不清楚组织硬度的这些变化是否可以调节TGF-β的作用。为此，我们检查了正常小鼠乳腺细胞和Madin-Darby犬肾上皮细胞，这些细胞在不同硬度的聚丙烯酰胺凝胶上培养并用TGF-β1处理。不同的基质刚性转换了对TGF-β1的功能反应。降低硬度增加TGF-β1诱导的细胞凋亡，而增加硬度导致EMT。基质刚性不改变Smad信号，而是调节PI 3 K/Akt信号通路。直接的遗传和药理学操作进一步证明了PI 3 K/Akt信号在凋亡和EMT反应中的作用。这些发现表明，基质刚性调节TGF-β诱导的细胞功能中先前未描述的转换，并提供了对疾病期间组织力学变化如何有助于细胞对TGF-β的反应的见解。
Matrix rigidity regulates a switch between TGF-β1–induced cell functions in two epithelial cell lines. On compliant polyacrylamide gels, TGF-β1 induced apoptosis, whereas on rigid gels, cells underwent an epithelial–mesenchymal transition (EMT). Compliant gels reduced PI3K/Akt activity, which was essential for cell survival and EMT on rigid gels. The transforming growth factor-β (TGF-β) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-β switches to promote tumorigenic cell functions, such as epithelial–mesenchymal transition (EMT) and increased cell motility. Dramatic changes in the cellular microenvironment are also correlated with tumor progression, including an increase in tissue stiffness. However, it is unknown whether these changes in tissue stiffness can regulate the effects of TGF-β. To this end, we examined normal murine mammary gland cells and Madin–Darby canine kidney epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-β1. Varying matrix rigidity switched the functional response to TGF-β1. Decreasing rigidity increased TGF-β1–induced apoptosis, whereas increasing rigidity resulted in EMT. Matrix rigidity did not change Smad signaling, but instead regulated the PI3K/Akt signaling pathway. Direct genetic and pharmacologic manipulations further demonstrated a role for PI3K/Akt signaling in the apoptotic and EMT responses. These findings demonstrate that matrix rigidity regulates a previously undescribed switch in TGF-β–induced cell functions and provide insight into how changes in tissue mechanics during disease might contribute to the cellular response to TGF-β.