FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity.
FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity.
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DOI：
10.1111/jcmm.13030
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发表时间：
2017-05
影响因子：
5.3
通讯作者：
Singh DP
中科院分区：
文献类型：
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作者：
Kubo E;Shibata S;Shibata T;Kiyokawa E;Sasaki H;Singh DP
转化生长因子β-2和成纤维细胞生长因子-2参与调节后囊混浊和其他上皮-间充质转化过程，如肿瘤进展、伤口愈合、组织纤维化和正常胚胎发育。我们之前使用了一个在体的啮齿动物PCO模型，显示在EMT过程中，原肌球蛋白(TPM)1/2的表达异常上调，从而重塑肌动蛋白细胞骨架。在这项体外研究中，我们发现TPM家族的细胞骨架蛋白参与调节和稳定肌动蛋白微丝(F-Actin)，并且在晶状体上皮细胞EMT过程中被转化生长因子β-2诱导。重要的是，我们发现转化生长因子β2和成纤维细胞生长因子2的作用是不同的。Tpm1/2小干扰RNA可逆转Tpm1/2诱导的应激性纤维形成和α-平滑肌肌动蛋白(α-β-SMA)的上调。成纤维细胞生长因子2可逆转转化生长因子β2诱导的Tpm1/2表达和应力纤维形成。此外，将成纤维细胞生长因子2转导到经转化生长因子β处理的晶状体上皮细胞后，通过重新激活丝裂原活化蛋白激酶/细胞外信号调节激酶通路，从而干扰细胞外信号转导，进而增强细胞外信号转导。相反，MEK抑制剂(PD98059)可减弱FGF2介导的Tpm1/2和α对SMA的抑制。然而，我们发现，接受EMT的正常晶状体上皮细胞在转化生长因子β和成纤维细胞生长因子2的联合刺激下表现出更强的迁移能力。这些发现可能有助于阐明PCO中形态发生EMT细胞增殖和纤维再生过程中肌动蛋白细胞骨架重新编程的机制。我们认为，了解FGF2、Tpm1/2的表达水平与转化生长因子βS驱动的子宫内膜间质转化之间的生理联系，可能为基于Tpm1/2的PCO的治疗策略的制定提供线索(S)。
Transforming growth factor (TGF) β2 and fibroblast growth factor (FGF) 2 are involved in regulation of posterior capsule opacification (PCO) and other processes of epithelial–mesenchymal transition (EMT) such as cancer progression, wound healing and tissue fibrosis as well as normal embryonic development. We previously used an in vivo rodent PCO model to show the expression of tropomyosin (Tpm) 1/2 was aberrantly up‐regulated in remodelling the actin cytoskeleton during EMT. In this in vitro study, we show the Tpms family of cytoskeleton proteins are involved in regulating and stabilizing actin microfilaments (F‐actin) and are induced by TGFβ2 during EMT in lens epithelial cells (LECs). Importantly, we found TGFβ2 and FGF2 played contrasting roles. Stress fibre formation and up‐regulation of α‐smooth muscle actin (αSMA) induced by TGFβ2 could be reversed by Tpm1/2 knock‐down by siRNA. Expression of Tpm1/2 and stress fibre formation induced by TGFβ2 could be reversed by FGF2. Furthermore, FGF2 delivery to TGFβ‐treated LECs perturbed EMT by reactivating the mitogen‐activated protein kinase (MAPK)/ extracellular signal‐regulated kinase (ERK) pathway and subsequently enhanced EMT. Conversely, MEK inhibitor (PD98059) abated the FGF2‐mediated Tpm1/2 and αSMA suppression. However, we found that normal LECs which underwent EMT showed enhanced migration in response to combined TGFβ and FGF2 stimulation. These findings may help clarify the mechanism reprogramming the actin cytoskeleton during morphogenetic EMT cell proliferation and fibre regeneration in PCO. We propose that understanding the physiological link between levels of FGF2, Tpm1/2 expression and TGFβs‐driven EMT orchestration may provide clue(s) to develop therapeutic strategies to treat PCO based on Tpm1/2.