KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1
KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1
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KLF6 通过 E2F1 的转录抑制抑制透明细胞肾细胞癌的转移
DOI：
10.1158/0008-5472.can-16-0348
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Zhang, Xu
中科院分区：
文献类型：
--
作者：
Gao, Yu;Li, Hongzhao;Zhang, Xu
转录因子KLF6在多种人类癌症的发生和转移中具有重要作用。矛盾的是，KLF6 表达在原发性转移性透明细胞肾细胞癌 (ccRCC) 中减弱，因此尚不清楚 KLF6 在这种情况下如何影响恶性进展。在这项研究中，我们证明肾细胞中 KLF6 的减弱足以促进 E2F1 介导的上皮间质转化和转移能力。在人类 ccRCC 的小鼠异种移植模型中，沉默 KLF6 会增加肿瘤细胞增殖和恶性特征，而沉默 E2F1 则逆转了这些特性。这些效应在转移模型系统中得到了证实，我们观察到大量由 ccRCC 细胞形成的肺转移灶，其中 KLF6 被沉默，E2F1 被增强。对ccRCC临床标本的分析表明，低水平的KLF6和高水平的E2F1与ccRCC的发展密切相关。总的来说，我们的结果证实了激活 KLF6-E2F1 轴在侵袭性 ccRCC 中的重要性，定义了一种驱动人类 ccRCC 侵袭和转移的新型关键信号机制。 (C) 2016 年 AACR。
The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelial-mesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. (C) 2016 AACR.