Dataset Information

MiR-210-5p promotes epithelial-mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells.

ABSTRACT: Osteosarcoma (OS) is a malignant bone tumor which occurs mainly in adolescents with frequent pulmonary metastasis and a high mortality rate. Accumulating evidence has indicated that microRNAs (miRNAs) play a vital role in various tumors by modulating target genes as well as signal pathways, and aberrant expression of miRNAs may contribute to OS progression. This study aimed to determine the association between miR-210-5p expression and OS progression and to investigate its potential underlying mechanism. Using reverse transcription-polymerase chain reaction (RT-PCR), miR-210-5p was found to be upregulated in clinical OS specimens and cell lines. Further functional analysis demonstrated that miR-210-5p promoted epithelial-mesenchymal transition (EMT) and induced oncogenic autophagy. Luciferase reporter assay, RNA-ChIP, and western blot analysis confirmed that PIK3R5, an essential regulator in the AKT/mTOR signaling pathway, is a target downstream gene of miR-210-5p. Overexpression or knockdown of PIK3R5 reversed the functional role of overexpression or knockdown of miR-210-5p, respectively. Silencing autophagy-related gene 5 (ATG5) abolished the functional effects of miR-210-5p upregulation or PIK3R5 knockdown in OS cells. In vivo, miR-210-5p overexpression promoted OS tumor growth and pulmonary metastasis. Taken together, our results demonstrated that miR-210-5p promoted EMT and oncogenic autophagy by suppressing the expression of PIK3R5 and regulating the AKT/mTOR signaling pathway. Therefore, inhibition of miR-210-5p may represent a promising treatment for OS.

SUBMITTER: Liu W

PROVIDER: S-EPMC7002725 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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miR-210-5p promotes epithelial-mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells.

Liu Wei W Jiang Dongdong D Gong Fangyi F Huang Yumin Y Luo Yongjun Y Rong Yuluo Y Wang Jiaxing J Ge Xuhui X Ji Chengyue C Fan Jin J Cai Weihua W

Cell death & disease 20200205 2

Osteosarcoma (OS) is a malignant bone tumor which occurs mainly in adolescents with frequent pulmonary metastasis and a high mortality rate. Accumulating evidence has indicated that microRNAs (miRNAs) play a vital role in various tumors by modulating target genes as well as signal pathways, and aberrant expression of miRNAs may contribute to OS progression. This study aimed to determine the association between miR-210-5p expression and OS progression and to investigate its potential underlying m ...[more]

PMID: 32024814

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Project description:Circular RNAs (circRNAs) have been demonstrated to be involved in osteosarcoma (OS) development; however, the underlying mechanism of circKMT2D in OS progression remains unclear. The present study aimed to elucidate how circKMT2D could affect hydrogen peroxide (H2O2)-induced OS progression. H2O2 (100 µmol/l) was used to treat MG63 and U2OS cells. The cell viability, invasive ability, apoptosis and circKMT2D expression were detected using Cell Counting Kit-8 assay, Transwell assay, flow cytometry and reverse transcription-quantitative PCR, respectively. Furthermore, MG63 and U2OS cells transfected with circKMT2D short hairpin RNA and negative control were treated with H2O2, and circKMT2D expression and cell phenotype were determined. Dual-luciferase reporter assay was conducted to determine the association between circKMT2D and miR-210 expression level. Rescue experiments were conducted to examine the mechanisms through which circKMT2D and miR-210 could affect H2O2-treated MG63 cells. In addition, the effects of miR-210 on the expression of the autophagy-related proteins Beclin1 and p62 in H2O2-treated MG63 cells were detected by western blotting. An autophagy inhibitor was used to treat the MG63 cells, and whether miR-210 could affect the H2O2-treated MG63 cell phenotype through autophagy was investigated. The results demonstrated that H2O2 treatment promoted cell apoptosis and decreased cell viability, invasive ability and circKMT2D expression in MG63 and U2OS cells. Furthermore, circKMT2D knockdown decreased the cell viability and invasive ability and enhanced the apoptosis of H2O2-treated MG63 and U2OS cells. circKMT2D possessed binding sites for miR-210 and inhibited miR-210 expression. In H2O2-treated MG63 cells, miR-210 silencing partially reversed the circKMT2D knockdown-induced cell viability inhibition and apoptosis promotion. In addition, miR-210 elevated Beclin1 expression and decreased p62 expression in H2O2-treated MG63 cells. The use of the autophagy inhibitor partially reversed the miR-210 overexpression-induced promotion of apoptosis and inhibition of the viability and invasive ability of H2O2-treated MG63 cells. Taken together, these findings indicated that circKMT2D knockdown may contribute to the inhibition of H2O2-attenuated OS progression via miR-210/autophagy pathway.

Project description:BackgroundThe investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.MethodsThe current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.ResultsWe demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3'-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.ConclusionsOur study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

Dataset Information

MiR-210-5p promotes epithelial-mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells.

Publications

miR-210-5p promotes epithelial-mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells.

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