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Exosome-transmitted lncRNA PCGEM1 as a "scaffold" for invasion and metastasis in gastric cancer.

18 Background: It is a major challenge that the hypoxia microenvironment can induce gastric cancer (GC).Understanding the underlying mechanisms and developing effective strategies against GC invasive and metastasis are highly desired in the clinic. Methods: GC cells were cultured under 1% O2 (HGC) and 20% O2 condition (NGC). NGC were co-cultured with HGC- medium. Exosomes from GC were extracted by ultracentrifugation. Electron microscopy images, western-blot and NanoSight particletracking used to analysis the size distributions and number of exosomes. Exosomal long noncoding RNA (lncRNA) profiling was performed using a lncRNA array. The “R” was used to recognize the differentially expressed lncRNAs (DELs). RNA-pulldown and mass spectrometry analysis were recruited to investigate the binding protein of target lncRNA. Results: Compared to NGC, HGC was more capable of invasion and metastasis which was evaluated by scrape and transwell. And HGC-medium induced NGC dissociation. Differential analysis revealed that lncRNA PCGEM1 was specifically expressed in HGC exosomes. PCGEM1 was up-regulated in GC cell and tissue. And the luciferase report confirmed HIF-1α, as a transcription factor, can bind to the promoter sequence of PCGEM1, promotes the overexpression of PCGEM1 in GC. Dii tracer proved that HGC-derived exosomes could be absorbed by NGC. RNA pull-down assay and mass spectrometry analysis showed that SNAI1 and USP9X with PCGEM1 directly. Conclusions: Our results suggest that the overexpressed of HIF-1α can up-regulated the expression of lncRNA PCGEM1 under hypoxia condition. And part of the overexpression PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and metastasis of other GC cells. The mechanism was that PCGEM1 can bind both USP9X and SNAI1 at the same time, and under the effect of deubiquitination enzyme USP9X, the expression of SNAI1 increased, thus promoting EMT and thereby promoted the invasion and metastasis of GC cells.