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信号通路在PVR上皮-间质转化中的作用
Release Time：2020-05-23增生性玻璃体视网膜病变（PVR）是接受血源性视网膜脱离（RRD）手术的患者失败的主要原因。 PVR的特征是在眼内形成异常的收缩膜，可引起视网膜牵引性脱离。上皮到间质转化（EMT）是上皮细胞牵连的主要病理过程，其中上皮细胞在形态学和表型上分化为间充质细胞。在此过程涉及的各种细胞类型中，视网膜色素上皮细胞是主要的贡献者，尽管经过数十年的研究，EMT的潜在机制仍然难以捉摸。最近，已证明信号传导途径（其中一些涉及生长因子）有助于EMT。在本文中，我们回顾了迄今为止有关此类信号转导作用的研究，包括转化生长因子-β，肝细胞生长因子，血小板衍生的生长因子和Notch，Wnt /β-catenin和河马。 -PVR的EMT中的信号通路。
d4并易位至细胞核，在此发挥功能。非经典途径包括有丝分裂原激活激酶（MAPK），细胞外信号调节激酶1/2（ERK1 / 2）和磷脂酰肌醇3激酶（PI3-K）/ AKt（也称为PKB，蛋白激酶B） ）/ mTOR（雷帕霉素的哺乳动物靶标）[11,12]。 MAPK非经典信号通路涉及三个成分：p38 MAP激酶，c-Jun N末端激酶（JNK）和p42 / 44 ERK。各自发挥自己的生物学功能。
TGF-β具有三种同工型：TGF-β1，TGF-β2和TGF-β3。主要同工型是TGF-β2。 TGF-β2的浓度高于其他同工型，TGF-β2的浓度与收缩力之间有很强的相关性[13-15]。在具有TGF-β2的人视网膜色素上皮（ARPE-19）细胞系中诱导EMT的模型系统中，上皮标记物（例如E-钙黏着蛋白和ZO-1）的表达减少，间充质标记物（例如α- SMA和纤连蛋白[16,17]。其他数据表明，TGF-β2激活了其他有助于PVR的生长因子[5,13]。 TGF-β1首先被描述为在各种上皮细胞中调节EMT [18]，尽管TGF-β1的浓度较低，并且诱导的EMT较TGF-β2诱导的低，但它也可能促成EMT。
最近，各种抑制PVR EMT的方法已经针对了TGF-β信号通路。一个例子是TricostatinA（TSA），它是组蛋白脱乙酰基酶（HDACs）的I和II类抑制剂[19-21]。 HDAC抑制剂已在包括炎症和癌症在内的各种治疗适应症中进行了研究[22,23]，并在几种细胞系中具有抗纤维化作用。 TSA不仅通过典型的TGF-β/ Smad途径而且通过非典型的途径抑制TGF-β诱导的EMT [11]。此外，磷酸化Smads中间接头的p38 MAP激酶也参与Smad信号通路[24]。已证明p38 MAP激酶抑制剂可阻断TGF-β诱导的EMT [9,25]。总之，阻断TGF-β信号传导的方法因此可以抑制EMT的过程。
HGF信号转导
HGF是一种多效性生长因子，有助于维持视网膜稳态和正常的视网膜功能[26]。在血清饥饿模型中，诱发了涉及HGF及其受体c-Met，EMT活化的病理状况。这一发现暗示HGF信号通路是EMT的潜在贡献者[27]。然而，自相矛盾的是，当比较有或没有PVR的RRD中的白介素和生长因子水平时，HGF没有差异[28]。此外，一些人假设HGF抑制RPE的转分化[3,29]。综上，这些发现表明，关于PVR中HGF的真正功能和HGF / c-Met信号通路的问题仍然存在。生长因子表达的阶段特异性可能是一个因素。关于HGF在PVR中期以最高水平表达的观察，可能是由除RPE和神经胶质细胞以外的其他未识别细胞类型引起的，为该问题带来了新的观点[4]。
PDGF信号转导
PDGF家族由五个配体组成，PDGF-AA，PDGF-BB，PDGF-AB，PDGF-CC和PDGF-DD。这些生长因子可以各自将PDGF受体（PDGFR）亚基二聚为同二聚体或异二聚体（PDGFRα，PDGFRβ或PDGFRαβ）。许多研究表明PDGF和PVR之间存在关联，并报道了人类PVR膜中激活的PDGFRs [30,31]。尽管PDGF是玻璃体中所有生长因子和细胞因子中含量最高的，但迄今为止，中和PDGF未能阻止实验性PVR [3,32,33]。最新数据表明，PDGFRα可以被比其他受体亚型更大的玻璃体生长因子激活，在实验性PVR中是必需的，抑制PDGFRα的激活可以阻止PVR的发展[30,33,34]。玻璃体生长因子被认为是非PDGF，能够间接激活PDGFRα，从而驱动PVR [3,33]。关于这种间接激活的性质，证据表明非PDGF通过涉及活性氧（ROS）和Src家族激酶（SFK）的细胞内机制激活PDGFRα[3,35]。这些发现表明，PDGFRα和相关途径的抑制剂作为预防PVR发展的潜在靶标具有吸引力。
Jagged/Notch signaling
The Jagged/Notch signaling pathway participates in many physiologic and pathologic processes including embryonic development, cancer metastasis, and fibrotic diseases [14,16]. In recent years, this pathway has also been implicated in the EMT that occurs in RPE cells. Although this association is not yet certain, accumulating evidence indicates that components of the Jagged/Notch signaling pathway, including Jagged-1, Notch-3, and downstream target genes Hes-1 and Hey-1, are upregulated in RPE cells during TGF-β2-activated EMT [11,14]. Studies modulating the Notch pathway, including through knockdown or overexpression of Jagged-1, showed that the EMT induced by TGF-β2 was closely linked to Jagged/Notch activation [14].These data indicate that, in addition to the canonical Smad and non-Smad pathways, the Jagged/Notch signaling pathway may also mediate TGF-β2-activated EMT. To further elucidate the pathological mechanism, there is increasing evidence that crosstalk between Smad and Jagged/Notch signaling pathways contributes to TGF-β2-activated EMT [14,16].
Wnt/β-catenin signaling
The Wnt signaling pathway, which is pivotal in cell motility and differentiation, mediates various diseases including PVR. Wnt exerts its function in a paracrine fashion. The canonical Wnt-signaling pathway proceeds as a cascade reaction, initiated when Wnt protein ligands bind to Frizzled and low density lipoprotein receptor-related protein (LRP) receptors on the cell surface. This induces activation of the cytoplasmic phosphoprotein Dishevelled (Dvl) and inhibits the GSK-3/APC/Axin-degradation complex. Dvl activation transduces signals to downstream components, leading to β-catenin accumulation in the cytoplasm and its subsequent translocation to the nucleus. β-Catenin in the nucleus interacts with transcription factor T-cell factor (TCF) and/or lymphoid enhancer factor (LEF), promoting expression of specific genes. Therefore, β-catenin translocation is regarded as being a key molecular event leading to EMT [36].
The Wnt/β-catenin signaling pathway has been primarily studied because of its effects on cadherins, transmembrane glycoproteins that modulate tissue movement [37]. β-Catenin binds to the cytoplasmic domain of cadherins [38-40]. When cadherin binding is disrupted, the release and nuclear translocation of β-catenin results in signaling activation. In this regard, inhibitors of β-catenin signaling may be a promising approach to prevent PVR [38,39].
Hippo signaling
The Hippo-signaling pathway influences cell growth and proliferation as well as contact inhibition. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo pathway. TAZ, also referred as WW-domain containing transcriptional regulator 1 (WWTR1), was first reported as a 14–3-3 binding protein [41,42]. TAZ is regarded as a paralog of YAP, and the two share some overlapping functions. However, compared with YAP, TAZ interacts with more DNA-binding transcription factors, including polyomavirus T antigens, TTF-1, TBX5, and Pax3 because of the structural and characteristic differences between the two proteins. TAZ, therefore, can participate in a wide range of biologic processes such as cell proliferation and migration. TAZ can also contribute to human cancers, including breast, ovarian, colorectal, lung, and brain tumors [43]. In recent studies, overexpression of YAP/TAZ-induced EMT during metastatic progression of tumor cells. These reports discussed potential roles of growth factors such as CTGF and the EGFR ligand and speculated on further mechanisms yet to be unraveled [43,44]. Thus far, there has not been any research specifically addressing the role of Hippo signaling in PVR.
Conclusion
PVR, which is characterized by the formation of a fibrotic contractile membrane, still remains a significant post-surgical complication for patients with RRD. It is clear that research toward understanding the complex pathogenic mechanism of PVR is still in its infancy and faces many challenges. However, work in recent decades has led to achievements in understanding several key signaling pathways. These include those pathways activated by TGF-β-, HGF-, and PDGF- as well as Notch-, Wnt/β-catenin-, and Hippo-signaling pathways. Though each has its respective functions, these signaling pathways can also interact with one other, potentially contributing to the pathogenesis of PVR [16]. Among these, the TGF-β-signaling pathway, especially that of TGF-β2, has drawn the most attention in PVR. Inhibiting these signaling pathways would be a potential therapeutic strategy for blocking EMT, thus preventing PVR. However, because growth factors are multifunctional cytokines and their inhibition might cause considerable side effects, individual signaling pathways should be targeted with cautiousness. Clearly, increased understanding of these complex pathways remains a priority for future preven
d4并易位至细胞核，在此发挥功能。非经典途径包括有丝分裂原激活激酶（MAPK），细胞外信号调节激酶1/2（ERK1 / 2）和磷脂酰肌醇3激酶（PI3-K）/ AKt（也称为PKB，蛋白激酶B） ）/ mTOR（雷帕霉素的哺乳动物靶标）[11,12]。 MAPK非经典信号通路涉及三个成分：p38 MAP激酶，c-Jun N末端激酶（JNK）和p42 / 44 ERK。各自发挥自己的生物学功能。
TGF-β具有三种同工型：TGF-β1，TGF-β2和TGF-β3。主要同工型是TGF-β2。 TGF-β2的浓度高于其他同工型，TGF-β2的浓度与收缩力之间有很强的相关性[13-15]。在具有TGF-β2的人视网膜色素上皮（ARPE-19）细胞系中诱导EMT的模型系统中，上皮标记物（例如E-钙黏着蛋白和ZO-1）的表达减少，间充质标记物（例如α- SMA和纤连蛋白[16,17]。其他数据表明，TGF-β2激活了其他有助于PVR的生长因子[5,13]。 TGF-β1首先被描述为在各种上皮细胞中调节EMT [18]，尽管TGF-β1的浓度较低，并且诱导的EMT较TGF-β2诱导的低，但它也可能促成EMT。
最近，各种抑制PVR EMT的方法已经针对了TGF-β信号通路。一个例子是TricostatinA（TSA），它是组蛋白脱乙酰基酶（HDACs）的I和II类抑制剂[19-21]。 HDAC抑制剂已在包括炎症和癌症在内的各种治疗适应症中进行了研究[22,23]，并在几种细胞系中具有抗纤维化作用。 TSA不仅通过典型的TGF-β/ Smad途径而且通过非典型的途径抑制TGF-β诱导的EMT [11]。此外，磷酸化Smads中间接头的p38 MAP激酶也参与Smad信号通路[24]。已证明p38 MAP激酶抑制剂可阻断TGF-β诱导的EMT [9,25]。总之，阻断TGF-β信号传导的方法因此可以抑制EMT的过程。
HGF信号转导
HGF是一种多效性生长因子，有助于维持视网膜稳态和正常的视网膜功能[26]。在血清饥饿模型中，诱发了涉及HGF及其受体c-Met，EMT活化的病理状况。这一发现暗示HGF信号通路是EMT的潜在贡献者[27]。然而，自相矛盾的是，当比较有或没有PVR的RRD中的白介素和生长因子水平时，HGF没有差异[28]。此外，一些人假设HGF抑制RPE的转分化[3,29]。综上，这些发现表明，关于PVR中HGF的真正功能和HGF / c-Met信号通路的问题仍然存在。生长因子表达的阶段特异性可能是一个因素。关于HGF在PVR中期以最高水平表达的观察，可能是由除RPE和神经胶质细胞以外的其他未识别细胞类型引起的，为该问题带来了新的观点[4]。
PDGF信号转导
PDGF家族由五个配体组成，PDGF-AA，PDGF-BB，PDGF-AB，PDGF-CC和PDGF-DD。这些生长因子可以各自将PDGF受体（PDGFR）亚基二聚为同二聚体或异二聚体（PDGFRα，PDGFRβ或PDGFRαβ）。许多研究表明PDGF和PVR之间存在关联，并报道了人类PVR膜中激活的PDGFRs [30,31]。尽管PDGF是玻璃体中所有生长因子和细胞因子中含量最高的，但迄今为止，中和PDGF未能阻止实验性PVR [3,32,33]。最新数据表明，PDGFRα可以被比其他受体亚型更大的玻璃体生长因子激活，在实验性PVR中是必需的，抑制PDGFRα的激活可以阻止PVR的发展[30,33,34]。玻璃体生长因子被认为是非PDGF，能够间接激活PDGFRα，从而驱动PVR [3,33]。关于这种间接激活的性质，证据表明非PDGF通过涉及活性氧（ROS）和Src家族激酶（SFK）的细胞内机制激活PDGFRα[3,35]。这些发现表明，PDGFRα和相关途径的抑制剂作为预防PVR发展的潜在靶标具有吸引力。
Jagged/Notch signaling
The Jagged/Notch signaling pathway participates in many physiologic and pathologic processes including embryonic development, cancer metastasis, and fibrotic diseases [14,16]. In recent years, this pathway has also been implicated in the EMT that occurs in RPE cells. Although this association is not yet certain, accumulating evidence indicates that components of the Jagged/Notch signaling pathway, including Jagged-1, Notch-3, and downstream target genes Hes-1 and Hey-1, are upregulated in RPE cells during TGF-β2-activated EMT [11,14]. Studies modulating the Notch pathway, including through knockdown or overexpression of Jagged-1, showed that the EMT induced by TGF-β2 was closely linked to Jagged/Notch activation [14].These data indicate that, in addition to the canonical Smad and non-Smad pathways, the Jagged/Notch signaling pathway may also mediate TGF-β2-activated EMT. To further elucidate the pathological mechanism, there is increasing evidence that crosstalk between Smad and Jagged/Notch signaling pathways contributes to TGF-β2-activated EMT [14,16].
Wnt/β-catenin signaling
The Wnt signaling pathway, which is pivotal in cell motility and differentiation, mediates various diseases including PVR. Wnt exerts its function in a paracrine fashion. The canonical Wnt-signaling pathway proceeds as a cascade reaction, initiated when Wnt protein ligands bind to Frizzled and low density lipoprotein receptor-related protein (LRP) receptors on the cell surface. This induces activation of the cytoplasmic phosphoprotein Dishevelled (Dvl) and inhibits the GSK-3/APC/Axin-degradation complex. Dvl activation transduces signals to downstream components, leading to β-catenin accumulation in the cytoplasm and its subsequent translocation to the nucleus. β-Catenin in the nucleus interacts with transcription factor T-cell factor (TCF) and/or lymphoid enhancer factor (LEF), promoting expression of specific genes. Therefore, β-catenin translocation is regarded as being a key molecular event leading to EMT [36].
The Wnt/β-catenin signaling pathway has been primarily studied because of its effects on cadherins, transmembrane glycoproteins that modulate tissue movement [37]. β-Catenin binds to the cytoplasmic domain of cadherins [38-40]. When cadherin binding is disrupted, the release and nuclear translocation of β-catenin results in signaling activation. In this regard, inhibitors of β-catenin signaling may be a promising approach to prevent PVR [38,39].
Hippo signaling
The Hippo-signaling pathway influences cell growth and proliferation as well as contact inhibition. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo pathway. TAZ, also referred as WW-domain containing transcriptional regulator 1 (WWTR1), was first reported as a 14–3-3 binding protein [41,42]. TAZ is regarded as a paralog of YAP, and the two share some overlapping functions. However, compared with YAP, TAZ interacts with more DNA-binding transcription factors, including polyomavirus T antigens, TTF-1, TBX5, and Pax3 because of the structural and characteristic differences between the two proteins. TAZ, therefore, can participate in a wide range of biologic processes such as cell proliferation and migration. TAZ can also contribute to human cancers, including breast, ovarian, colorectal, lung, and brain tumors [43]. In recent studies, overexpression of YAP/TAZ-induced EMT during metastatic progression of tumor cells. These reports discussed potential roles of growth factors such as CTGF and the EGFR ligand and speculated on further mechanisms yet to be unraveled [43,44]. Thus far, there has not been any research specifically addressing the role of Hippo signaling in PVR.
Conclusion
PVR, which is characterized by the formation of a fibrotic contractile membrane, still remains a significant post-surgical complication for patients with RRD. It is clear that research toward understanding the complex pathogenic mechanism of PVR is still in its infancy and faces many challenges. However, work in recent decades has led to achievements in understanding several key signaling pathways. These include those pathways activated by TGF-β-, HGF-, and PDGF- as well as Notch-, Wnt/β-catenin-, and Hippo-signaling pathways. Though each has its respective functions, these signaling pathways can also interact with one other, potentially contributing to the pathogenesis of PVR [16]. Among these, the TGF-β-signaling pathway, especially that of TGF-β2, has drawn the most attention in PVR. Inhibiting these signaling pathways would be a potential therapeutic strategy for blocking EMT, thus preventing PVR. However, because growth factors are multifunctional cytokines and their inhibition might cause considerable side effects, individual signaling pathways should be targeted with cautiousness. Clearly, increased understanding of these complex pathways remains a priority for future preven
