Hyaluronan metabolism is associated with DNA repair genes in breast and colorectal cancer

INA SEVIC; FIORELLA SPINELLI; DAIANA VITALE; ANTONELLA ICARDI; PAULA GIANNONI; CAROLINA CRISTINA; LAURA ALANIZ

Conferencia; 13th conference of the International Society for Hyaluronan Sciences; 2021

ISHAS

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 functions1. 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 the epigenetic changes2,3. 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 HYAL1 levels in the breast but not colorectal cancer. We also show lower HA levels in tumor compared with normal tissue that could indicate a possible influence of tumor on its surrounding ?normal? tissue. In both breast and colorectal cancer, CD44 and BRCA2 showed a strong positive correlation. We also investigated the relationship between the mRNA expression and the patient survival using the Kaplan?Meier Plotter database. The data for breast cancer showed that the mRNA expression levels of BRCA1 and 2 are higher in cancer than normal tissue and are significantly associated with the relapse-free survival (RFS). CD44 expression is associated with RFS even though there are no significant differences in expression levels, while HYAL1 levels are higher in normal tissue but don?t influence survival. In gastric cancer Kaplan?Meier Plotter data showed that the BRCA1 and 2 levels are higher in cancer than normal tissue and are significantly associated with the overall survival time (OS), whereas HAS2 and CD44 levels don?t differ between normal and cancer tissue but, nevertheless, influence patient survival. Lastly, STRING analysis was used to evaluate a possible protein interaction networks 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 in the molecular mechanisms of the development and the progression of cancer.References: 1. Lu, P., et al. J Cell Biol, 2012. 196(4): p. 395-406.2. Zhou, L., et al. Mol Cancer Res, 2013. 11(3): p. 272-81.3.Phelan, C.M., et al.. Br J Cancer, 2014. 110(2): p. 530-4.