Stress-Induced Changes in the Methylation Status of Mmp1 and Mmp8 Genes in Tumor Tissue of Rats with Guerin Carcinoma

Abstract

Background. Chronic stress is a key determinant of public health, signifi  antly impacting regulatory systems and potentially contributing to carcinogenesis. Chronic stress, through the activation of the hypothalamic-pituitary- adrenal axis and glucocorticoid signaling, can modify the epigenetic landscape of cells, including DNA meth- ylation. Th s study aimed to evaluate whether chronic glucocorticoid-induced stress modulates the methylation status of the promoter regions of the Mmp1 and Mmp8 genes in the tumor tissue of rats with Guerin carcinoma. Materials and Methods. to simulate chronic stress, dexamethasone (DEX) was administered subcutaneously to laboratory rats with transplanted Guerin carcinoma. tumor samples were collected on days 7, 14, and 21 of tumor growth. The methylation status of the Mmp1 and Mmp8 gene promoters was analyzed using methylation-specifi PCR. The level of methylation was quantifi  d as the ratio of methylated to unmethylated PCR products, expressed as a percentage. Results. In the control group (Guerin carcinoma without DEX), the Mmp1 promoter was hypo- methylated (38—40% methylation) throughout the observation period. DEX administration led to a further slight decrease in Mmp1 methylation to 32%, though insignifi  ant. In contrast, the Mmp8 promoter in tumor tissue showed baseline methylation levels of 55—57%. Under the influence of DEX, Mmp8 hypermethylation was ob- served as early as day 7 (61%) and signifi  antly progressed by day 14 (67%) and day 21 (69%). Conclusion. Our study demonstrated that chronic glucocorticoid-induced stress altered the epigenetic profile of tumor cells by in- ducing differential methylation of the matrix metalloproteinase genes. Specifi  ally, it promoted the maintenance of Mmp1 hypomethylation and signifi  antly increased the Mmp8 promoter hypermethylation. These fi  dings suggest that chronic stress may contribute to an aggressive tumor phenotype through the epigenetic regulation of extracel- lular matrix remodeling.