BackgroundCircRNA has emerged as a new non-coding RNA that plays crucial roles in tumour initiation and development. ‘MiRNA sponge’ is the most reported role played by circRNAs in many tumours. The AKT/mTOR axis is a classic signalling pathway in cancers that sustains energy homeostasis through energy production activities, such as the Warburg effect, and blocks catabolic activities, such as autophagy. Additionally, the AKT/mTOR axis exerts a positive effect on EMT, which promotes tumour metastasis.MethodsWe detected higher circNRIP1 expression in gastric cancer by performing RNA-seq analysis. We verified the tumour promotor role of circNRIP1 in gastric cancer cells through a series of biological function assays. We then used a pull-down assay and dual-luciferase reporter assay to identify the downstream miR-149-5p of circNRIP1. Western blot analysis and immunofluorescence assays were performed to demonstrate that the circNRIP1-miR-149-5p-AKT1/mTOR axis is responsible for the altered metabolism in GC cells and promotes GC development. We then adopted a co-culture system to trace circNRIP1 transmission via exosomal communication and RIP experiments to determine that quaking regulates circNRIP1 expression. Finally, we confirmed the tumour suppressor role of microRNA-133a-3p in vivo in PDX mouse models.ResultsWe discovered that knockdown of circNRIP1 successfully blocked proliferation, migration, invasion and the expression level of AKT1 in GC cells. MiR-149-5p inhibition phenocopied the overexpression of circNRIP1 in GC cells, and overexpression of miR-149-5p blocked the malignant behaviours of circNRIP1. Moreover, it was proven that circNRIP1 can be transmitted by exosomal communication between GC cells, and exosomal circNRIP1 promoted tumour metastasis in vivo. We also demonstrated that quaking can promote circNRIP1 transcription. In the final step, the tumour promotor role of circNRIP1 was verified in PDX models.ConclusionsWe proved that circNRIP1 sponges miR-149-5p to affect the expression level of AKT1 and eventually acts as a tumour promotor in GC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0935-5) contains supplementary material, which is available to authorized users.

BackgroundAutophagy plays a crucial role in sustaining the homeostasis in various malignant diseases. It has also been reported to promote tumor development in multiple cancers. Glutaminolysis instead of Warburg Effect produce adequate ATP and provide nitrogen and carbon to replenish the TCA cycle which has been discovered to be a new energy source for tumor cells recently. By means of degrading intracellular particles including amino acids, nucleotides, fatty acids, sugars and aged organisms, autophagy can recycle the aforementioned particles into bioenergetics and biosynthesis pathways, finally favoring tumor cells. MicroRNA is a kind of noncoding RNA that regulates the targeting gene expression mostly at post-transcription level. Among these miRNAs, microRNA-133a-3p is reported to be a tumor suppressor in numerous cancers.MethodsWe characterized the down-regulated expression level of microRNA-133a-3p in gastric cancer via TCGA database. Subsequently, we verified the tumor suppressor role of microRNA-133a-3p in gastric cancer cells through a series biological function assay. We used immunofluorescence and transmission electron microscope to observe the negative effect of microRNA-133a-3p on autophagy and used dual-luciferase report assay to identify the candidate gene GABARAPL1 of microRNA-133A-3p.Then we used high performance liquid phase mass spectrometry and seahorse analysis to detect whether miR-133a-3p could block the glutaminolysis metabolism through autophagy. At last, we confirmed the tumor suppressor role of microRNA-133a-3p in vivo on PDX mice model.ResultsWe demonstrated that microRNA-133a-3p overexpression could block the activation of autophagy to ruin the abnormal glutaminolysis and further inhibit the growth and metastasis of gastric cancer cells. We successfully proved gastric cancer cells can replenish glutaminolysis via autophagy and microRNA-133a-3p could block aforementioned pathway by targeting core autophagy participants GABARAPL1 and ATG13.We then verified the negative function of microRNA-133a-3p on autophagy-mediated glutaminolysis both in PDX model and human gastric cancer organoid model.ConclusionsMicroRNA-133a-3p targets GABARAPL1 to block autophagy-mediated glutaminolysis, further repressing gastric cancer growth and metastasis.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0993-y) contains supplementary material, which is available to authorized users.

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