HYALURONAN METABOLISM IS ASSOCIATED WITH DNA REPAIR GENES IN BREAST AND COLORECTAL CANCER.

INA SEVIC; DAIANA L. VITALE; CANDELA MORÁN; BRANDONE A; PAOLO ROSALES; ANTONELA ICARDI; ROMANO LUCIA; GIANNONI P; CRISTINA CAROLINA; ALANIZ LAURA

Rosario

Congreso; SAIB 2023; 2023

The tumor microenvironment (TME) plays an important role in the progression of cancer and represents a significant factor that should be considered in the study of this pathology. TME is composed of cellular and non-cellular components that coexist in altered homeostasis. The key non-cellular component is the extracellular matrix (ECM), a complex network of macromolecules with different biological functions. Among the components of the ECM that are altered in tumors is the glycosaminoglycan Hyaluronic Acid (HA). Several studies have reported a relationship between the level of HA and the aggressiveness of cancer. On the other hand, it has been shown that changes in the microenvironment can lead to changes in the expression of some genes. The BRCA1 and BRCA2 genes have been extensively studied in different tumors and the alterations in ECM can lead to the fixation of different mutations or epigenetic changes. In this work, we compared mRNA levels of HA metabolism members and BRCA genes, between tumor and non-tumor adjacent tissue in breast and colorectal cancer, and its correlation with clinical biomarkers (ER, PR, HER2 and KI67). We show alteration in HA metabolism in colorectal but not breast cancer. However, we found a decrease in CD44, BRCA1 and 2 protein levels in the breast but not colorectal cancer. We also show lower HA levels in tumor compared to normal tissue that could indicate a possible influence of tumor on its surrounding “normal” tissue. Additionally, we investigated the relationship between the expression of BRCA 1 and 2 genes and HA metabolism in cell culture. We observed that the decrease in HA synthase (HAS2) level increases the expression of BRCA 1 and 2 in MDA-MB-231 cells. Lastly, STRING analysis was used to evaluate a possible protein interaction network between HA metabolism members and BRCA genes. The analysis showed two clusters: HA metabolism (HAS2, HAS3, HYAL1, HYAL2, CD44) and DNA repair and regulation (BRCA1, BRCA2, TP53, EP300) with CD44 as a link between these processes. In summary, our results demonstrate the association between HA metabolism and the DNA repair genes, BRCA1 and 2 which could give us a new insight into the molecular mechanisms of the development and the progression of cancer.