Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation.
Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation.
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DOI：
10.1186/s13046-021-01870-5
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发表时间：
2021-02-23
期刊：
影响因子：
--
通讯作者：
Singh AB
中科院分区：
文献类型：
--
作者：
Kumar B;Ahmad R;Giannico GA;Zent R;Talmon GA;Harris RC;Clark PE;Lokeshwar V;Dhawan P;Singh AB
紧密连接蛋白-2表达在多种癌症中上调并促进癌症恶性度。值得注意的是，肾细胞系中claudin-2表达的调节与其他器官中报道的调节形成对比。然而，claudin-2在肾透明细胞癌（RCC）中的作用仍然未知，尽管其主要表达在近端小管上皮（PTE），RCC起源的网站。公开可用的和独立的患者数据库检查了密蛋白-2与RCC的相关性。通过功能获得或丧失测定在体外和体内验证新蛋白质功能。通过质谱、免疫沉淀和突变研究以及功能评价得出机制结果。我们表明紧密连接蛋白-2表达的显著降低表征了PTE细胞和经历去分化的离体培养的小鼠肾脏。在这些模型中，claudin-2的抑制足以诱导间充质可塑性和侵袭性移动性。此外，claudin-2表达的进行性丧失与RCC进展和患者存活率差相关。在RCC衍生的癌细胞中过表达claudin-2抑制肿瘤发生能力和异种移植肿瘤生长。这些数据支持密蛋白-2在RCC中的新的肿瘤抑制作用。机制的见解进一步揭示了claudin-2与YAP蛋白缔合并调节其磷酸化（S127）和核表达。在缺失其PDZ结合基序后，封闭蛋白-2表达的肿瘤抑制作用丧失，这强调了PDZ结构域在封闭蛋白-2与雅普相互作用中调节RCC恶性肿瘤的关键作用。我们的研究结果证明了claudin-2蛋白的新的肾特异性肿瘤抑制作用，并进一步证明claudin-2与雅普信号传导在调节RCC恶性肿瘤中协同作用。在线版本包含补充材料，可通过10.1186/s13046-021-01870-5获得。
Claudin-2 expression is upregulated in multiple cancers and promotes cancer malignancy. Remarkably, the regulation of claudin-2 expression in kidney cell lines contrasts its reported regulation in other organs. However, claudin-2 role in renal clear cell carcinoma (RCC) remains unknown despite its predominant expression in the proximal tubular epithelium (PTE), the site of RCC origin. Publicly available and independent patient databases were examined for claudin-2 association with RCC. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by Mass spectroscopy, immunoprecipitation and mutational studies, and functional evaluations. We show that the significant decrease in claudin-2 expression characterized PTE cells and Ex-vivo cultured mouse kidney subjected to dedifferentiation. Inhibition of claudin-2 was enough to induce mesenchymal plasticity and invasive mobility in these models. Further, a progressive loss of claudin-2 expression associated with the RCC progression and poor patient survival. Overexpression of claudin-2 in RCC-derived cancer cells inhibited tumorigenic abilities and xenograft tumor growth. These data supported a novel tumor-suppressive role of claudin-2 in RCC. Mechanistic insights further revealed that claudin-2 associates with YAP-protein and modulates its phosphorylation (S127) and nuclear expression. The tumor suppressive effects of claudin-2 expression were lost upon deletion of its PDZ-binding motif emphasizing the critical role of the PDZ-domain in claudin-2 interaction with YAP in regulating RCC malignancy. Our results demonstrate a novel kidney specific tumor suppressive role for claudin-2 protein and further demonstrate that claudin-2 co-operates with the YAP signaling in regulating the RCC malignancy. The online version contains supplementary material available at 10.1186/s13046-021-01870-5.
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三个紧密连接相关的Maguks ZO-1，ZO-2和ZO-3与Claudins的Cooh Termini直接结合。
DOI：
10.1083/jcb.147.6.1351
发表时间：
1999-12-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Itoh M;Furuse M;Morita K;Kubota K;Saitou M;Tsukita S
通讯作者：
Tsukita S
人类多能干细胞的肾单位祖细胞和肾脏器官的产生。
影响因子：
14.8
作者：
Morizane R;Bonventre JV
通讯作者：
Bonventre JV
影响因子：
4.8
作者：
Dan, Qinghong;Shi, Yixuan;Szaszi, Katalin
通讯作者：
Szaszi, Katalin
影响因子：
3.3
作者：
Medici, D;Hay, ED;Goodenough, DA
通讯作者：
Goodenough, DA
单个基因产物Claudin -1或-2，在成纤维细胞中重构紧密结合的连接链和新兵。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Fujimoto, K;Tsukita, S
通讯作者：
Tsukita, S