Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin
Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin
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DOI：
10.1091/mbc.e08-06-0566
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发表时间：
2009-02-01
影响因子：
3.3
通讯作者：
Maxwell, Patrick H.
中科院分区：
文献类型：
--
作者：
Harten, Sarah K.;Shukla, Deepa;Maxwell, Patrick H.
上皮到间质转化（EMT）在肾脏发育、纤维化和癌症中很重要。肿瘤抑制因子VHL功能的丧失导致EMT的许多特征，并且已经假设关键介质是粘附连接（AJ）蛋白E-cadherin的下调。本研究表明，与正常肾脏相比，VHL功能丧失对VHL缺陷透明细胞肾细胞癌（CCRCC）细胞的紧密连接（TJ）成分occludin和claudin 1的体外表达和VHL缺陷散发性CCRCC的体内表达也有显著影响。在种系VHL突变患者肾脏的癌前病灶中，Occludin也下调，这与CCRCC的起始一致。重新表达E-cadherin足以恢复AJ，但不能恢复TJ组装，表明TJ缺陷与E-cadherin下调无关。另外的实验表明，缺氧诱导因子（HIF）的激活有助于TJ和AJ异常，因此VHL/HIF途径有助于EMT表型的多个方面，而这些方面并不相互依赖。尽管这些缺陷具有独立的性质，但我们发现，用组蛋白去乙酰化酶抑制剂丁酸钠（抑制HIF激活）治疗，在VHL失活的情况下，提供了一种逆转EMT的方法。
Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation.