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.

RAB27A promotes melanoma cell invasion and metastasis via regulation of pro‐invasive exosomes

“…RAB27A tumor-dependency may also be largely restricted to melanoma, given that RAB27A protein has been shown to be enriched in melanoma compared to other cancer types, both in cell lines 53 and patient tissue. 54 However, studies have also implicated RAB27A in colon cancer, 55 breast cancer, 31,56 glioma, 57 pancreatic cancer, 58 hepatocellular carcinoma 59 and bladder cancer. 60 Here we have highlighted the role of RAB27A in promoting exosome-mediated invasion and metastasis in melanoma.…”

“…Archival tissue pathology specimens identified from the Melanoma Institute Australia (MIA) Research Database as matching fresh-frozen tissue specimens banked by the MIA Biobank and included in The Cancer Genome Atlas (TCGA) project were utilized (n = 95, from which 63 patients had sufficient tumor tissue for evaluation of RAB27A staining). Criteria for inclusion of MIA patients in the TCGA project were AJCC stage III (n = 55) or stage IV (n = 8) at time of collection from and follow-up data were retrieved from the MIA Research Database.…”

Rab27A overexpression promotes bladder cancer proliferation and chemoresistance through regulation of NF-κB signaling

“…Rab27A depletion decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis of melanoma cells [ 9 ]. Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion [ 10 ]. Rab27a expression was significantly associated with grade progression and worse prognosis in all grades of gliomas [ 11 ].…”

Rab27a Regulates Human Perivascular Adipose Progenitor Cell Differentiation

“…Using this approach, we identified numerous secretion-associated proteins that appeared to be enriched in human PVAT compared to including human subcutaneous white adipose tissue, including synaptotagmin-1, myosin-9, Rab11 and Rab27 (data not shown). Importantly, Rab27a is a well-established regulator of protein secretion and degradation [20, 27, 37], and regulates the function of multiple systems [38], including pancreatic beta cell release of insulin [22], VEGFR1 degradation during angiogenesis [39], cancer stem cell self-renewal [40], initiation of clotting cascades [41] and lytic granule exocytosis from cytotoxic T-cells [42]. Rab27a expression and function has not been studied in adipose tissue, and given its prominent role in regulating secretion, we validated expression in human PVAT.…”

“…Interestingly, PVAT-APC expression of Rab27a regulates their ability to undergo adipogenesis, and siRNA-mediated knockdown of Rab27a caused impaired adipogenesis and lipid mobilization. Rab27a has been shown to regulate progenitor cell self-renewal of breast and colon cancers via effects on secretion [40, 52]. Given these findings, it is feasible to speculate that Rab27a may regulate PVAT expansion during obesity.…”