21P - Immune cells can cause inappropriate inflammation leading to the miRNAome shift and cell transformation

Abstract

Aim/Background: Overall, macrophages and some subtypes of lymphoid cells are found in tumour stroma. These cells secrete a variety of growth factors, proinflammatory cytokines and chemokines, esp. TNF-a, IL-1b and IL-6, causing the formation of inflammatory microenvironment around tumour cells. TNF-a and IL-1b signaling increases activity of NF-kB pathway. At the same time, IL-6, triggers JAK-STAT signaling pathway, which effector is STAT3. NF-kB and STAT3 activity facilitates hyperexpression of miRNAs miR-155, miR-181 and miR-21 as well as down-regulates expression of miRNAs miR-15/16, miR-199 and let-7. This investigation aims to identify in what way these shifts in miRNAome can lead to epigenome reorganization supporting the cell transformation. Methods: MiRNA targets within gene transcripts were predicted in silico using TargetScan software. Results: Overexpressed miRNA miR-155 can suppress APC gene. As a result, beta-catenin avoids degradation and translocates into the nucleus. Therefore, miR-155 hyperexpression derepresses and enhances Wnt pathway signaling and, moreover, causes spontaneous ligand-independent activity of the pathway leading to the reactivation of stemness genes. Transcripts of HDAC2/4/8/9 and SIRT1/5 genes encoding histone deacetylases carry targets for at least one of up-regulated miRNAs miR-155, miR-181 or miR-21. Also, these miRNAs can silence EZH1, MLL, MLL3, NSD1, SETD6/7/8, SMYD1, SUV39H2 genes encoding histone methyltransferases. MiRNA miR-21 suppresses gene encoding de novo DNA methyltransferase DNMT3B. At the same time, down-regulation of miRNA miR-15/16 can allow hyperexpression of gene encoding acetyltransferase Elp3. These shifts cause the increase of overall level of chromatin acetylation and expression and, therefore, create epigenetic background for reactivation of silent transposons, oncogenes and stemness genes as well as other genes important for cell transformation. Conclusions: Immune system can paradoxically facilitate the tumour growth instead of healing. Cancer-related inflammation leads to the miRNAome and epigenome shifts contributing to the cell transformation and following tumour growth. Legal entity responsible for the study: Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine Funding: Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine Disclosure: All authors have declared no conflicts of interest.