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CircNRIP1 acts as a sponge of miR-1200 to suppress osteosarcoma progression via upregulation of MIA2.

ABSTRACT: Circular RNAs (circRNAs), a class of non-coding RNAs, play an essential role in embryo development and carcinogenesis, circNRIP1 was recently identified to promote development of multiple human cancers. This study investigated the role of circNRIP1 in osteosarcoma (OS) cells and the potential mechanisms relating to the sponging miRNAs and their target genes. OS cell lines and normal human osteoblasts were grown for qRT-PCR analysis of circNRIP1 expression and functions of circNRIP1 expression in OS cell proliferation, migration, and invasion in vitro. Bioinformatics analysis was then performed to predict the sponge miRNA of circNRIP1 and the target gene, which was confirmed by using the dual-luciferase reporter assay. The in vivo functions of circNRIP1 was evaluated in OS cell xenograft models, while levels of relevant marker genes were examined using immunohistochemistry. CircNRIP1 was mainly localized in OS cell cytoplasm and significantly lower in OS cell lines than in normal human osteoblasts. CircNRIP1 overexpression significantly inhibited OS cell proliferation, migration, and invasion in vitro. miR-1200 was predicted as the sponge miRNA of circNRIP1 and directly interacted with circNRIP1 confirmed by the dual-luciferase reporter assay. Moreover, miR-1200 overexpression significantly alleviated the inhibitory effect of circNRIP1 on OS cells. A protein-coding gene MIA2 was identified as the miR-1200 targeting gene and reversely associated with miR-1200 expression in OS cells. Increase in MIA2 expression in a murine OS cell xenograft model was associated with circNRIP1 expression in inhibition of OS cell xenograft growth in vivo. These data support the circNRIP1 OS-suppressive role by sponge of miR-1200 expression and in turn to upregulate MIA2 expression.

SUBMITTER: Hei R

PROVIDER: S-EPMC9251688 | 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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CircNRIP1 acts as a sponge of miR-1200 to suppress osteosarcoma progression via upregulation of MIA2.

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