Özkan Didem
Nigde Ömer Halisdemir University, Faculty of Medicine, Medical Biology, Nigde, Turkey.
Istanbul Okan University, Vocational School of Health Service, Istanbul, Turkey.
Taiwan J Obstet Gynecol. 2023 Mar;62(2):311-324. doi: 10.1016/j.tjog.2022.09.010.
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.
肿瘤相关巨噬细胞上的TAM受体（TYRO3、AXL和MerTK）及其配体是大多数实体癌很有前景的治疗靶点。然而，在子宫内膜癌（最常见的侵袭性妇科恶性肿瘤）中，TAM受体介导的激活途径、其分子机制及其病理生理学尚不清楚。本研究的目的是揭示子宫内膜癌中TAM受体和配体的全面基因概况。
使用提供来自癌症基因组图谱（TCGA）数据的生物信息学工具，获取子宫体子宫内膜癌（UCEC）队列（n = 509）的突变和表达谱。使用PolyPhen-2和SNAP工具预测UCEC中已鉴定突变的致癌/致病特性。进行STRING网络分析以更好地了解细胞过程中突变蛋白的功能关系。除了突变谱外，还确定了基因表达和生存谱。最后，使用TIMER工具研究靶基因与巨噬细胞浸润之间的相关性。
在6个基因中总共检测到229个突变，其中81个错义突变具有致病性。在UCEC队列中，患者组中MerTK、AXL、GAS6和PROS1的表达水平在统计学上显著低于健康组，而患者组中CD47的表达水平高于健康组（p < 0.01）。蛋白质-蛋白质相互作用分析确定了靶基因，SRC蛋白负责细胞增殖、黏附和迁移等重要细胞机制，ITGB3、ITGAV和THSB1蛋白参与内皮-间质转化和肿瘤代谢重编程，FOLR1参与DNA复制和损伤修复。
我们认为TAM受体及其配体可能是治疗子宫内膜癌有吸引力的分子靶点，因为它们作为免疫细胞的多效性抑制剂，有效调节凋亡细胞的吞噬清除，并使肿瘤微环境成为更适合肿瘤生长的生态位。
