微管蛋白乙酰化在TGF-β介导的上皮细胞间充质转分化（EMT）过程中的作用及调控机制

Epithelial-mesenchymal transition(EMT) is a process by which fully differentiated epithelial cells undergo a phenotypic conversion and assume a mesenchymal cell phenotype. In physiological states, the EMT is associated with wound healing and tissue regeneration, and in pathological states, it is associated with organ fibrosis and tumor metastasis. The mechanism of EMT is still unknown, but TGF-β is considered as one of the most important factors to induce EMT.Microtubules are a component of the cytoskeleton that is not only involved in cell division, but that also contributes to many features of cytosplasm structuration in interphase cells, including by organizing and compartmentalizing certain signalling pathways. Acetylated α-tubulin was found to be consecutive to MT stabilization. It plays an important role of cell morphology and migration. Our project seeks to elucidate the mechanism and function of acetylated α-tubulin underlying TGF-β induced EMT. We wish to determide if acetylated α-tubulin involved in EMT. This study will not only explain the relationship among TGF-β, acetylated α-tubulin and EMT, but also provide insights into potential therapeutics for prevention and treatment of disease such as cancer and fibrosis.

上皮细胞-间充质转化（EMT）表现为上皮细胞失去上皮特征，并获得间充质特性。在正常的生物体内，EMT过程在胚胎发育过程和损伤修复过程中发挥关键性的作用。在病理状态，EMT被认为是纤维化疾病和肿瘤转移的一个重要成因。目前EMT的发生以及逆转的精确机制尚不清楚，TGF-β被认为是诱导EMT最重要的因子。微管蛋白作为细胞骨架的重要组成部分，不仅参与了细胞分裂的整个过程，而且决定了细胞各个时期的细胞形态以及结构。α-微管蛋白的乙酰化形式已证实是微管蛋白结构稳定的一种状态,对细胞的形态以及迁移都起着重要作用。本课题计划在细胞水平上证实α-微管蛋白乙酰化与TGF-β介导的EMT过程的关系。明确α-微管蛋白乙酰化是否参与到EMT过程中，并深入讨论其机制。本研究将会解释α-微管蛋白乙酰化与EMT发生发展的关系以及信号通路，为肿瘤或纤维化疾病的治疗提供一种新的思路和药物作用新靶点。

上皮细胞-间充质转化（EMT）表现为上皮细胞失去自身的特点，并获得间充质细胞的特性，包括上皮细胞极性的丢失、细胞骨架的重排以及迁移能力和侵袭能力的获得。TGF-beta被认为是诱导EMT最重要的因子，但具体精确机制尚不十分清楚。微管蛋白tubulin作为细胞骨架的重要组成部分，参与了细胞分裂的过程，也在细胞各个时期对细胞结构都起着重要作用。它的乙酰化对于微管蛋白结构稳定、细胞形态以及迁移起着重要作用，但其是否参与了EMT的诱导和维持仍然知之甚少。在本项研究中，冯新华实验室发现在TGF-beta介导的EMT过程中伴随着alpha-tubulin乙酰化水平的降低。进一步的研究发现TGF-beta增加alpha-tubulin去乙酰化酶HDAC6的活性。TGF-beta受体抑制剂、HDAC6抑制剂或HDAC6敲减可以抑制alpha-tubulin去乙酰化，同时抑制EMT过程的发生。我们的结果表明，去乙酰化酶HDAC6在EMT过程的调控中起着重要的作用，同时证明alpha-tubulin的乙酰化水平可以作为EMT的标志物。