MicroRNAs and target genes as regulators of colon cancer immune signaling

Colorectal cancer (CRC) is among the most common oncological diseases in the world, associated with a high mortality rate. Recently, immunotherapeutic approaches to the treatment of CRC have been developed, which have enabled achievement of long-term and stable remission in a certain group of patients. The success of immunotherapy depends on the immune processes associated with oncogenesis in the colon. The key role in modulating immune environment of the tumor is played by the activity of genes regulating differentiation and functions of immune cells, as well as by a variety of microRNAs that perform posttranscriptional expression control of target genes. In this regard, the aim of our work was to study the expression profiles of immune-associated genes and microRNAs to determine the immune signaling mechanisms of colon cancer and search for potential therapeutic targets. The study included 18 persons (12 women, 6 men, median age – 66 years) diagnosed with colon cancer, having been treated at the National Medical Research Center of Oncology in 2018-2019. All tumors had microsatellite instability status. The transcription profiles of microRNAs and immune response genes were determined by next-generation sequencing. The study has revealed 28 differentially expressed microRNAs in the tumor tissues, including 15 microRNAs with increased expression and 13 microRNAs with decreased expression. Of the 395 genes examined, 156 were differentially expressed, including 62 genes with increased expression and 94 genes with decreased activity. Identification of cell populations based on the transcriptional pattern of tumors has discerned four types of immune cells: neutrophils, B lymphocytes, CD8⁺T lymphocytes, and M1 macrophages. Neutrophils were the most common cell type (16 of 18 samples). A stepwise analysis of possible relationships between transcriptional patterns allowed us to select 713 miRNA-mRNA pairs. After filtering by validated interactions, 24 such pairs were found. On this basis, a miRNA-mRNA interaction network was constructed, which could be involved into the regulation of multiple immune signaling mechanisms and cell cycle control. Most of the revealed signaling pathways contained CDK1, for which therapeutic inhibitors are known, being at different stages of clinical trials. The possibilities of influencing CDK1 described in the present work may be used for further clinical studies and development of therapeutic strategies employing selective molecular suppression of immunemediated carcinogenesis in colorectal cancer.

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