Abstract
BackgroundEmerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear.MethodsWe analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR’s regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments.ResultsWe found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling.ConclusionOur study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.
Highlights
Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis
We aimed to study the link between HOX transcript antisense RNA (HOTAIR) and exosome secretion-related genes
We showed that the expression levels of RAB35, synaptosome associated protein 23 (SNAP23), and vesicle associated membrane protein 3 (VAMP3) were significantly higher in hepatocellular carcinoma (HCC) tissues than in normal tissues (Fig. 1c–e)
Summary
Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. The role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear. Yang et al Molecular Cancer (2019) 18:78 with cargos during tumorigenesis [7, 8]; the molecular mechanisms of exosome secretion in tumor cells remain unclear. The biogenesis of exosomes is generated from the inward budding of the membranes of multivesicular bodies (MVBs) to form intraluminal vesicles (ILVs), which mature and are contained within MVBs [9] This process involves various sorting machineries, including endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent processes [10]. Multiple intracellular trafficking steps are required to regulate MVB motility, docking, and fusion with the plasma membrane, which involve different effectors and molecular mechanisms [11]. Different Rab GTPases localize in distinct subcellular locations and are specific to cell types; the molecular mechanisms of Rab GTPases’ effects on exosome secretion in tumor cells require further study
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