Podocalyxin EBP50 Ezrin Molecular Complex Enhances the Metastatic Potential of Renal Cell Carcinoma Through Recruiting Rac1 Guanine Nucleotide Exchange Factor ARHGEF7
Podocalyxin EBP50 Ezrin Molecular Complex Enhances the Metastatic Potential of Renal Cell Carcinoma Through Recruiting Rac1 Guanine Nucleotide Exchange Factor ARHGEF7
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DOI：
10.2353/ajpath.2010.090539
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发表时间：
2010-06-01
影响因子：
6
通讯作者：
Jou, Tzuu-Shuh
中科院分区：
文献类型：
--
作者：
Hsu, Yung-Ho;Lin, Wei-Ling;Jou, Tzuu-Shuh
Podocalyx最初被发现存在于肾小球足细胞中，以关键地维持肾小球超滤装置的结构和功能的完整性。最近，它已经成为来自各种组织来源的肿瘤的恶性标志物。通过免疫组织化学方法，我们发现9.6%的肾癌患者过表达该蛋白。这一亚组患者的疾病特异性和总生存期显著缩短，重要的是，我们通过多因素分析建立了足红素过度表达作为潜在远处转移的独立预后因素。通过小干扰RNA下调Podocalyin导致模型肾小管细胞有缺陷的迁移，这可以通过Podocalyin的重新表达而得到纠正。小的GTPase rac1的活性被Podocalysin基因敲除，这是一个很好地描述细胞迁移的调节器。相反，Podocalysin在人胚胎肾细胞中过表达上调rac1活性，这依赖于Podocalysin、ERM结合的磷蛋白50、Ezrin和ARHGEF7形成的复合体，ARHGEF7是rac1的激活剂。因此，Podocalyx可以作为一个生物标记物来识别具有较高转移潜能的肾癌患者，以便在临床的早期阶段进行更积极的干预。(Am J Pathol2010,176：3050-3061；DOI：10.2353/ajpath.2010.090539)
Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages. (Am J Pathol 2010, 176:3050-3061; DOI: 10.2353/ajpath.2010.090539)