Transcription factor Six2 induces a stem cell-like phenotype in renal cell carcinoma cells
Transcription factor Six2 induces a stem cell-like phenotype in renal cell carcinoma cells
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DOI：
10.1002/2211-5463.12721
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发表时间：
2019-10-01
期刊：
影响因子：
2.6
通讯作者：
Sun, Shuzhen
中科院分区：
文献类型：
--
作者：
Cheng, Na;Li, Hongjuan;Sun, Shuzhen
肾细胞癌（Renal cell carcinoma，RCC）占成人恶性肿瘤的2-3%，在过去的二十年中，RCC的全球发病率增加了约2%。同源异型盒蛋白Six 2已被证明可促进乳腺癌细胞的干细胞性，并在肾脏发育中发挥作用，但其参与RCC进展之前尚未研究。在这里，我们发现Six 2在RCC组织中的表达显著增加，并且与RCC患者的总生存率呈负相关。此外，six 2的表达水平明显高于正常肾细胞。功能实验表明，six 2基因敲低减弱了RCC细胞的干细胞性，这是明显的减少球体形成能力和干细胞性标志物（sox 2和nanog）的表达。机制研究表明Six 2直接与sox 2的增强子结合，促进sox 2的表达和nanog下游效应子的表达。此外，sox 2的过表达挽救了six 2对RCC细胞干细胞的抑制作用。值得注意的是，在RCC组织中six 2表达与sox 2和nanog表达正相关。总的来说，我们的结果指向一个six 2/sox 2轴负责RCC细胞的干细胞。
Renal cell carcinoma (RCC) accounts for 2-3% of adult malignant tumors, and the incidence of RCC worldwide has increased by about 2% over the past two decades. The homeobox protein Six2 has been shown to promote the stemness of breast cancer cells and play a role in kidney development, but its involvement in RCC progression has not previously been investigated. Here, we found that six2 expression was significantly increased in RCC tissues and negatively correlated with the overall survival of patients with RCC. In addition, six2 expression exhibited a remarkably higher level relative to that in normal renal cells. Functional experiments showed that six2 knockdown attenuated the stemness of RCC cells, which was evident by decreased spheroid formation ability and stemness marker (sox2 and nanog) expression. Mechanistic studies indicated that Six2 directly bound to the enhancer of sox2, promoting sox2 expression and downstream effector expression of nanog. Furthermore, overexpression of sox2 rescued the inhibitory effects of six2 on the stemness of RCC cells. Notably, six2 expression is positively correlated with sox2 and nanog expression in RCC tissues. Collectively, our results point toward a six2/sox2 axis responsible for RCC cell stemness.