CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling
CCT6A suppresses SMAD2 and promotes prometastatic TGF-β signaling
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CCT6A 抑制 SMAD2 并促进促转移性 TGF-β 信号传导
DOI：
10.1172/jci90439
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发表时间：
2017-05-01
影响因子：
15.9
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
Ying, Zhe;Tian, Han;Li, Mengfeng
矛盾的是，在许多癌症类型的早期肿瘤发展过程中，TGF-β 充当肿瘤抑制因子，而在这些癌症的晚期阶段，TGF-β 表达增加与高转移和不良预后有关。这些发现表明，未知的机制可能会重新连接 TGF-β 信号，使其发挥其在癌细胞中的促转移作用。我们目前使用非小细胞肺癌 (NSCLC) 细胞系、动物模型和临床标本的研究表明，在 SMAD3 功能完整的情况下，抑制 SMAD2 可将 TGF-β 诱导的转录反应转变为前转移状态。重要的是，我们鉴定出含有 TCP1 亚基 6A (CCT6A) 的伴侣蛋白作为 SMAD2 的抑制剂和直接结合蛋白，并发现 CCT6A 抑制 NSCLC 细胞中的 SMAD2 功能并促进转移。此外，选择性抑制 SMAD3 或 CCT6A 可有效抑制 TGF-β 介导的转移。我们的研究结果提供了一种将 TGF-β 信号转导至其促转移臂的机制，并可能有助于开发针对 TGF-β 的非小细胞肺癌治疗策略。
Paradoxically, during early tumor development in many cancer types, TGF-beta acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-beta expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-beta signaling toward its prometastatic role in cancer cells. Our current study using non-small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-beta-induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-beta-mediated metastasis. Our findings provide a mechanism that directs TGF-beta signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-beta for NSCLC.