Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion
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Feixue Feng1,2,*,Yinghao Jiang1,*, Huanyu Lu3,*, Xiaozhao Lu1, Shan Wang1, Lifeng Wang4, Mengying Wei4, Wei Lu1, Zhichao Du1, Zichen Ye1, Guodong Yang4, Fang Yuan2, Yanxia Ma2, Xiaoying Lei1, Zifan Lu1
1The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi’an, China
2Department of Clinical Laboratory, the Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
3Department of Occupational and Environmental Health, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
4The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
*These authors contributed equally to this work
Zifan Lu, email: [email protected]
Xiaoying Lei, email: [email protected]
Keywords: Rab27A, colon cancer stem cells, NF-κB, secretion of cytokines, microenvironment
Received: May 13, 2016 Accepted: August 11, 2016 Published: August 20, 2016
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.
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