Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion.
Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion.
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DOI：
10.18632/oncotarget.11454
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发表时间：
2016-09-27
期刊：
影响因子：
--
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Feng F;Jiang Y;Lu H;Lu X;Wang S;Wang L;Wei M;Lu W;Du Z;Ye Z;Yang G;Yuan F;Ma Y;Lei X;Lu Z
最近的证据揭示了肿瘤干细胞（CSC）在致瘤性中的关键作用，但CSC和肿瘤环境之间的相互作用如何帮助维持CSC启动仍然不清楚。小GTP酶Rab 27 A通过监测细胞外囊泡的胞吐作用来调节自分泌和旁分泌细胞因子，并且据报道促进某些肿瘤进展。我们观察到Rab 27 A的过表达通过增加HT 29细胞系中CD 44+和PKH 26 high细胞的比例来增加球体形成效率（SFE），并且加速具有更高百分比的S期细胞的Colosphere的生长。机制研究显示Rab 27 A过表达后的HT 29细胞培养上清能够扩增细胞，增加VEGF和TGF-β的分泌。在裸鼠移植瘤模型中，Rab 27 A可提高肿瘤的成瘤率，增大肿瘤体积，并有明显的血管生成。作为对比，敲除Rab 27 A削弱了上述效应。更重要的是，在结肠球中检测到较高的p65水平与Rab 27 A之间的相关性，p65足以诱导Rab 27 A的上调，并且证实Rab 27 A启动子中存在功能性NF-κB结合位点。综上所述，我们的研究结果揭示了一种独特的机制，即肿瘤环境相关的NF-κB信号通过一种放大的旁分泌机制促进结肠癌干细胞（cCSCs）的各种特性，这种机制受较高Rab 27 A水平的调节。
Recent evidences have unveiled critical roles of cancer stem cells (CSCs) in tumorigenicity, but how interactions between CSC and tumor environments help maintain CSC initiation remains obscure. The small GTPases Rab27A regulates autocrine and paracrine cytokines by monitoring exocytosis of extracellular vesicles, and is reported to promote certain tumor progression. We observe that overexpression of Rab27A increased sphere formation efficiency (SFE) by increasing the proportion of CD44+ and PKH26high cells in HT29 cell lines, and accelerating the growth of colosphere with higher percentage of cells at S phase. Mechanism study revealed that the supernatant derived from HT29 sphere after Rab27A overexpression was able to expand sphere numbers with elevated secretion of VEGF and TGF-β. In tumor implanting nude mice model, tumor initiation rates and tumor sizes were enhanced by Rab27A with obvious angiogenesis. As a contrast, knocking down Rab27A impaired the above effects. More importantly, the correlation between higher p65 level and Rab27A in colon sphere was detected, p65 was sufficient to induce up-regulation of Rab27A and a functional NF-κB binding site in the Rab27A promoter was demonstrated. Altogether, our findings reveal a unique mechanism that tumor environment related NF-κB signaling promotes various colon cancer stem cells (cCSCs) properties via an amplified paracrine mechanism regulated by higher Rab27A level.