Genetic and epigenetic bases of prostate tumor cell radioresistance

Radiation therapy plays a leading role in the treatment of prostate cancer, but the emergence of radioresistant forms of this disease dictates the need for a personalized ap-proach based on the data from genetic and epigenetic markers. Such markers include the copy number variation as well as gene and microRNA expression.

The aim of the study was to validate the list of potential predictors of radioresistance of prostate tumor cells in a model experiment based on the determination of gene copy number variation, gene transcriptional activity and microRNA expression.

The study used a PC-3 prostate cancer cell culture. The determination of the relative copy number variation and expression of 32 genes (BRCA1, BRCA2, PTEN, CASP3, CASP8, BAX, BCL2, CASP9, P53, MDM2, AKT1, ATM, BRIP1, CDK1, CDKN1B, CCND1, CCND3, FGFR2, KU70, RAD50, RAP80, Rif1, RNF168, TopBP1, HIST, H2AX, EXO1, XRCC4, RBBP8, EP300, LIG4, C-FLIP), as well as 15 microRNAs (let-7, miR15a/ 16, miR-17, miR-18a, miR-21, miR-24, miR-26b, miR-99a, miR-100, miR-101, miR-106a, miR-663a, miR-143, miR-145) was performed using the real-time quantitative polymerase chain reaction method. It was found that daily irradiation of PC-3 cells on a Novalis TX linear accelerator at doses of 6 and 7 Gy for 5 days leads to a significant decrease in the total number of cells and the number of viable cells. Nevertheless, after 5 days of irradiation, about 15% of the initial number of prostate tumor cells retained their viability, which is due to their special genetic and epigenetic characteristics: increased copy number and expression of genes BRCA2, CDK1, CDKN1B, H2AX, RAD50, XRCC4, RBBP8 and EP300 and reduced copy number and expression of CCND3, TP53, and BCL2 genes, as well as differential expression of six microRNAs (hsa-miR-18a-5p, hsa-miR-24-5p, hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-145-5p, hsa-let-7a-3p).

This study enabled to identify genetic and epigenetic markers of prostate tumor cells resistance to radiation therapy.