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MiR-1287-5p has inhibitory effects on breast cancer growth mediated by interaction with phosphoinositide 3-kinase CB

ABSTRACT: Background: Non-coding RNAs and especially microRNAs have been discovered as master regulators of cancer initiation and progression. The aim of our study was to discover and characterize the function of yet uncharacterized microRNAs in human breast carcinogenesis. Methods: In an unbiased approach, we made use of a commonly used model system for breast cancer (BC) stem cells (“mammospheres”) to identify whole miRNome alterations with a special focus on previously uncharacterized miRNAs in BC. We further characterized the influence of microRNA-1287-5p, a yet uncharacterized microRNA in BC, in patient samples (n=1262) and on several hallmarks of cancer in vitro and in vivo with a special focus on triple negative BC. The molecular mode of action was further characterized using whole transcriptome analysis, in silico prediction tools, miRNA-interaction luciferase assays and pheno-copy assays. Results: We identified miR-1287-5p among many others as differentially expressed in mammospheres. Clinical validation indicated that miR-1287-5p is significantly downregulated in human BC and associated with poor prognosis. This clinical finding can be explained by miR-1287-5p mediated growth inhibitory effects, G1 cell cycle arrest, decreased anchorage-independent growth and tumor growth in vivo. Finally, we identified PIK3CB as a direct molecular interactor of miR-1287-5p and a pheno-copy factor for miR-1287-5p. Finally, targeting PI3K-signaling pathway with chemical inhibitors together with miR-1287-5p mimics increased the pharmacological growth inhibitory potential. Conclusion: In conclusion, our data identified for the first time an involvement of miR-1287-5p in human BC and suggest a potential for therapeutic interventions in hardly to treat triple negative BC.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE103218 | GEO | 2017/08/30

SECONDARY ACCESSION(S): PRJNA400558

REPOSITORIES: GEO

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Project description:Breast cancer (BC) is a commonly identified life-threatening type of cancer and a major cause of death among women worldwide. Several microRNAs (miRs), including miR-143-5p, have been reported to be vital for regulating hallmarks of cancer; however, the effect of miR-143-5p on BC requires further exploration. The present study performed bioinformatics analysis on GSE42072 and GSE41922 datasets from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database to identify miR-143-5p expression patterns. Furthermore, miR-143-5p expression was detected in BC cell lines and tissues via reverse transcription-quantitative PCR. Post-transfection with miR-143-5p mimics, Cell Counting Kit-8, colony formation and Transwell assays were performed to explore the effects of miR-143-5p on BC cell proliferation, colony formation, and migration. The association of miR-143-5p with the hypoxia-inducible factor-1α (HIF-1α)-associated glucose transporter 1 (GLUT1) pathway was explored via western blotting, immunofluorescence and dual-luciferase reporter assay. The present study detected high expression of miR-143-5p in BC tissue of the GSE42072 and serum of the GSE41922 datasets by GEO chip analysis. Additionally, the expression levels of miR-143-5p were decreased in BC tissues compared with those in adjacent healthy tissues, and low miR-143-5p expression was associated with a poorer prognosis and shorter survival time in patients with BC. In vitro, miR-143-5p expression levels were decreased in BC cells, and transfection with miR-143-5p mimics suppressed BC cell proliferation, colony formation, migration. Furthermore, miR-143-5p targeted the HIF-1α-related GLUT1 pathway, and inhibited HIF-1α and GLUT1 expression. Additionally, HIF-1α agonists reversed the miR-143-5p-induced inhibition during tumorigenesis. In conclusion, miR-143-5p exhibited low expression in BC tissues, and suppressed BC cell proliferation, colony formation, migration. Moreover, the antitumor effects of miR-143-5p targeted the HIF-1α-related GLUT1 pathway.

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MiR-1287-5p has inhibitory effects on breast cancer growth mediated by interaction with phosphoinositide 3-kinase CB

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