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Circular RNA circUBE2J2 acts as the sponge of microRNA-370-5P to suppress hepatocellular carcinoma progression

ABSTRACT: Accumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in hepatocellular carcinoma is largely unknown. CircRNA microarray was performed to identify abnormally expressed circRNAs in HCC tissue samples. We conducted Kaplan–Meier survival analysis to explore the significance of circUBE2J2 in clinical prognosis. Then, we examined the functions of circUBE2J2 in HCC by cell proliferation, migration, and mouse xenograft assay. We identified miR-370-5P as a circUBE2J2-related microRNA by using biotin-labeled circUBE2J2 probe to perform RNA antisense purification (RAP) assay in HCC cells. The dual luciferase reporter assay and RNA pulldown assays were employed to verify the relationships among circUBE2J2, miRNA-370-5P, and KLF7. Microarray analysis and qRT-PCR verified a circRNA termed circUBE2J2 that was downregulated in HCC. Kaplan–Meier survival analysis showed that downregulated circUBE2J2 was correlated with poorer survival. CircUBE2J2 expression in HCC cells was selectively regulated via luciferase reporter assays; circUBE2J2 and KLF7 were observed to directly bind to miR-370-5P. Furthermore, knockdown of circUBE2J2 in HCC could downregulate KLF7, the target of miR-370-5P, thus promoting the proliferation and migration of HCC cells. Then the related experiment suggested that circUBE2J2 could regulate the expression of KLF7 by sponging miR-370-5p. In summary, we infer that circUBE2J2 may act as a competing endogenous RNA (ceRNA) to regulate KLF7 expression through sponging miR-370-5P and play a regulatory functions in HCC. CircUBE2J2 may be a diagnostic biomarker and potential target for HCC therapy.

SUBMITTER: Zhang L

PROVIDER: S-EPMC8536678 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Circular RNA circUBE2J2 acts as the sponge of microRNA-370-5P to suppress hepatocellular carcinoma progression

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