The influence of selected microRNAs on the expression profile of genes and proteins related to the tumor necrosis factor-alpha signaling pathways in endometrioid endometrial cancer

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Abstract
Purpose: Tumor necrosis factor exerts many adverse biological effects, from cell proliferation to cell death. Accurate diagnosis and treatment are therefore difficult due to many factors influencing tumor necrosis factor-alpha (TNF-α) signaling, including microRNAs (miRNAs), especially in tumors. The aim of the study was to determine the influence of miRNAs on the expression profile of genes and proteins related to TNF-α signaling in endometrial cancer. Methods: The material consisted of 45 endometrioid endometrial cancer and 45 normal endometrium tissue samples. Gene expression was determined with microarrays and then validated for TNF-α, tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2), caveolin 1 (CAV1), nuclear factor kappa B subunit 1 (NFKB1), and TGF-beta activated kinase 1 (MAP3K7)-binding protein 2 (TAB2) using real-time quantitative reverse transcription reaction (RT-qPCR). The protein concentration was assessed by enzyme-linked immunosorbent assay (ELISA). In addition, differentiating miRNAs were identified using miRNA microarrays and their relationships with TNF-α signaling genes were evaluated using the mirDIP tool. Results: TNF-α, TNFR1, TNFR2, CAV1, NFKB1, and TAB2 were upregulated both on the mRNA and protein levels. The decrease in the activity of miR-1207-5p, miR-1910-3p, and miR-940 may be related to CAV1 overexpression. Similarly for miR-572 and NFKB1 as well as miR-939-5p and TNF-α. In turn, miR-3178 may partially inhibit TNFR1 activity up to grade 2 cancer. Conclusion: TNF-α signaling, especially the TNF-α/NF-κB axis, is disrupted in endometrial cancer and worsens with disease progression. The observed changes may be the result of miRNAs’ activity in the initial stage of endometrial cancer and its gradual loss in later grades.

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