Twist1-induced activation of human fibroblasts promotes matrix stiffness by upregulating palladin and collagen α1(VI)
Twist1-induced activation of human fibroblasts promotes matrix stiffness by upregulating palladin and collagen α1(VI)
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DOI：
10.1038/onc.2016.57
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发表时间：
2016-10-06
期刊：
影响因子：
8
通讯作者：
Casal, J. I.
中科院分区：
文献类型：
--
作者：
Garcia-Palmero, I.;Torres, S.;Casal, J. I.
转录因子 Twist1 参与上皮-间质转化，并通过大多数未知的机制促进癌症转移。在结直肠癌中，Twist1 表达主要局限于肿瘤基质。我们发现，稳定转染 Twist1 的人成纤维细胞系获得了活化的癌症相关成纤维细胞 (CAF) 的特征，例如过度增殖、迁移能力增强以及肌动蛋白细胞骨架排列。此外，Twist1 激活的成纤维细胞促进基质硬度增加。使用定量蛋白质组学，我们确定 Palladin 和胶原蛋白 α 1(VI) 是成纤维细胞系中 Twist1 效应的两个主要介质。免疫共沉淀研究表明 Palladin 和 Twist1 在细胞核内相互作用，表明 Palladin 可以充当转录调节因子。 Palladin 与 Twist1 激活的成纤维细胞的细胞生物力学特性、方向和极性更相关，而胶原蛋白 α 1(VI) 与 Twist1 激活的成纤维细胞的迁移和侵袭能力更相关。据观察，palladin 和胶原蛋白 α 1(VI) 在结直肠 CAF 中过度表达，并且与结直肠癌患者生存率和复发预测较差相关。我们的结果表明，表达 Twist1 的成纤维细胞模仿了存在于肿瘤侵袭前沿的 CAF 的特性，这可能解释了 Twist1 的促转移活性。 Twist1 似乎需要 Palladin 和胶原蛋白 α 1(VI) 作为下游效应器来发挥其促转移作用，这可能是癌症转移的未来治疗靶点。
The transcription factor Twist1 is involved in the epithelial-mesenchymal transition and contributes to cancer metastasis through mostly unknown mechanisms. In colorectal cancer, Twist1 expression is mainly restricted to the tumor stroma. We found that human fibroblast cell lines stably transfected with Twist1 acquired characteristics of activated cancer-associated fibroblasts (CAFs), such as hyperproliferation, an increased ability to migrate and an alignment of the actin cytoskeleton. Further, Twist1-activated fibroblasts promoted increased matrix stiffness. Using quantitative proteomics, we identified palladin and collagen alpha 1(VI) as two major mediators of the Twist1 effects in fibroblast cell lines. Co-immunoprecipitation studies indicated that palladin and Twist1 interact within the nucleus, suggesting that palladin could act as a transcription regulator. Palladin was found to be more relevant for the cellular biomechanical properties, orientation and polarity, and collagen alpha 1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen alpha 1(VI) were observed to be overexpressed in colorectal CAFs and to be associated with poor colorectal cancer patient survival and relapse prediction. Our results demonstrate that Twist1-expressing fibroblasts mimic the properties of CAFs present at the tumor invasive front, which likely explains the prometastatic activities of Twist1. Twist1 appears to require both palladin and collagen alpha 1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis.