RESUMO
Here we report the results of the pilot project of exosomal miRNA expression levels in clear cell renal cell carcinoma (ccRCC) patients with different clinical response to ICIs (nivolumab) and treatment related toxicity. Immune-related adverse events (irAEs) are a major cause of immune checkpoint inhibitors cancellation and therapy failure. Modern studies demonstrate evidence that exosomes are of great importance in the formation of tumor resistance to ICIs drugs and therapy. We performed exosomal miRNA-146a expression analysis using qPCR on 86 ccRCC patients and revealed a statistically significant (p = 0.01) decreased expression level in ccRCC patients with CTCAE grade 3-4 (M±SEM 1.71 ± 0.13) compared to CTCAE grade 0-2 group (M±SEM 2.30 ± 0.24). The expression levels of miRNA-126, miRNA-218 and miRNA-410 did not show statistically significant differences in the comparison groups (p > 0.05). Association analysis of rs2910164 in the miRNA-146a gene demonstrated that CC genotype and C allele carriers had higher risk of developing severe irAEs (p = 0.03, OR = 6.12; p = 0.01, OR = 2.42, respectively) compare with GG and GC carriers. That is the first attempt to identify biomarkers of ICIs treatment efficacy for ccRCC in the Volga-Ural region based on exosomal miRNAs analysis.
RESUMO
BACKGROUND: Renal cell carcinoma is the most common form of kidney cancer in adults. DNA methylation of regulatory sequences at the genomic level and interaction between microRNAs and the messenger RNAs of target genes at the posttranscriptional level contribute to the dynamic regulation of gene activity. Aberrations in these mechanisms can result in impaired functioning of cell signaling pathways, such as that observed in malignant tumors. We hypothesized that microRNA genes methylation may be associated with renal cancer in patients. METHODS AND RESULTS: We examined methylation levels of 22 microRNA genes in tumor and normal kidney tissue of 30 patients with TNM Stage III clear cell renal cell carcinoma using a pathway-specific real-time polymerase chain reaction array (EpiTect Methyl II PCR Arrays, Qiagen). MicroRNA expression analysis by quantitative polymerase chain reaction was also performed. Significant differences in methylation levels were found in two genes and in two clusters of microRNA genes. MicroRNA-23b/-24-1/-27b, microRNA -30c-1/-30e and let-7 g was hypermetylated in clear cell renal cell carcinoma tissue, microRNA -301a was hypomethylated in tumor compared with the adjacent normal tissues. Expression of microRNA-301a, microRNA-23b in the clear cell renal cell carcinoma tissues was significantly overexpressed when compared with the adjacent normal tissues and let-7 g was significantly downregulated in tumor. CONCLUSIONS: Our results may indicate the contribution of microRNA-301a, microRNA-23b and let-7 g in the pathogenesis of renal cancer, but further studies are needed to determine the functional significance of the detected changes.
