Molecular profiling of TAM tyrosine kinase receptors and ligands in endometrial carcinoma: An in silico-study.

Abstract

TAM Receptors (TYRO3, AXL, and MerTK) and their ligands on tumor-associated macrophages are promising therapeutic targets for most solid cancers. However, in endometrial cancer, the most common invasive gynecologic malignancy, the TAM receptor-mediated activation pathway, its molecular mechanisms, and its pathophysiology are unknown. The goal of this research; to uncover the comprehensive genetic profile of TAM receptors and ligands in endometrial cancer. Mutation and expression profiles of the Uterine Corpus Endometrial Carcinoma (UCEC) cohort (n=509) were obtained using bioinformatics tools providing data from The Cancer Genome Atlas (TCGA). PolyPhen-2 and SNAP tools were used to predict the oncogenic/pathogenic properties of the identified mutations for UCEC. STRING network analysis was performed to better understand the functional relationships of the mutant proteins in cellular processes. Furthermore to the mutation profile, gene expression and survival profiles were also determined. Finally, the correlation between target genes and macrophage infiltration was investigated using the tool TIMER. A total of 229 mutations were detected in 6 genes, and 81 missense mutations are pathogenic. In the UCEC cohort, the expression level of MerTK, AXL, GAS6, and PROS1 was statistically significantly lower in the patient group, while the expression level of CD47 was higher in the patient group than in the healthy group (p<0.01). Protein-protein interaction analysis identified target genes, SRC protein responsible for important cellular mechanisms such as cell proliferation, adhesion and migration, ITGB3, ITGAV and THSB1 proteins involved in endothelial mesenchymal transition and tumor metabolism reprogramming, and FOLR1 involved in DNA replication and damage repair. We believe that TAM receptors and their ligands may be attractive molecular targets for the treatment of endometrial carcinoma because they act as pleiotropic inhibitors of immune cells, effectively regulate phagocytic clearance of apoptotic cells, and make the tumor microenvironment a more suitable niche for the tumour.