title: Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion.
abstract: 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.
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.|Department of Clinical Laboratory, the Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China.
authors.forename: Feixue
authors.initials: F
authors.lastname: Feng
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department 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.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Lu
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaozhao
authors.initials: X
authors.lastname: Lu
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Wei
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Du
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Zichen
authors.initials: Z
authors.lastname: Ye
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, the Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Clinical Laboratory, the Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lei
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China.
authors.forename: Zifan
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005089:Exocytosis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D013234:Stem Cells / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C497483:CD44 protein, human; D016207:Cytokines; D018960:Hyaluronan Receptors; D016328:NF-kappa B; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human
keywords: NF-κB; Rab27A; colon cancer stem cells; microenvironment; secretion of cytokines