The role of microRNAs in the development of radioresistance of prostate cancer cells (experimental study)

Abstract

Background. Radiation therapy is one of the leading treatments for early and late stage prostate cancer. Radiation therapy is one of the leading treatments for early and late stage prostate cancer. The significant frequency of prostate cancer progression after radiation therapy makes it relevant to study the molecular mechanisms of the development of radioresistance, to identify prognostic markers of its development.Objective: identification and analysis of the mechanism of action of microRNAs regulating radioresistance of prostate cancer cells on the model of the androgen-independent DU145 cell line.Materials and methods. We used human prostate adenocarcinoma cell lines: DU145-hormone-independent prostate cancer cell line and DU145-RR - its radioresistant variant. Differential microRNA expression was measured in cultured DU145 and DU145-RR cells 1, 8 days after a single gamma irradiation at a dose of 4 Gy. To analyze the differential expression of microRNAs in the initial and radioresistant variants of DU145 cells, the HiSeq 2000 platform (Illumina Inc., USA) was used. The miRBase v.21 database was used to identify microRNAs. The miRTarbase 7.0 and KEGG PATHWAY databases were used for bioinformatic analysisResults. The results of the study showed that the aberrant expression of miR-101-3p, -148a-3p, -21-3p, -532-5p, -92a-3p in DU145-RR cells upregulated compared to that in DU145 cells, and miR-125b-5p, -23a-3p, -424-3p - downregulated. It has been shown that the role of these microRNAs is associated with the provision of functional interaction between DNA methyltransferases, the transcriptional regulator of the proto-oncogenic protein Myc, and PTEN phosphatase in the regulation of the activity of MAPK and PI3K protein kinase signaling cascades. Constitutive activation of these cascades leads to an increase in cell survival, migration, proliferation, and growth.Conclusion. A wide range of target genes and a significant change in the expression profiles of microRNAs in various conditions, including the transition of malignant cells to a radioresistant status, makes microRNAs promising prognostic markers of radioresistance in prostate cancer.