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Öğe Comparative Analysis of the Mutation and Expression Profile of the Cytoprotective NRF2/KEAP1/P62/SQSTM1 Signaling Pathway in Different Glioma Subtypes: An In Silico Study(Galenos Publ House, 2023) Akin, Dilara Fatma; Aktas, Sedef HandeAim: The NRF2/KEAP1/p62/SQSTM1 pathway is the master regulator of antioxidant enzymes and detoxification proteins, both of which play a critical role in redox homeostasis. It shows that the this structurally active pathway has a crucial role in cancer as it inhibits tumorigenesis and metastatic processes and it induces pro-survival genes that promote chemoresistance. The relationship between the molecular mechanisms causing the pathway to malfunction and the development of brain tumors has yet to be fully clarified. The aim of this study is to analyze the genetic changes and expression level differences of the NRF2/KEAP1 pathway comparatively in low-grade gliomas (LGG) and glioblastoma multiforme (GBM) pathology. Materials and Methods: Gene expression profiles and DNA sequences of GBM (n=591) and LGG (n=511) patients and healthy tissue were downloaded from the TCGA database. Not only were gene expression and mutation patterns determined in this study, but also the impacts of genes on survival were assessed. PolyPhen-2 and SNAP tools were used to estimate the pathogenic properties of the changes identified. Results: A total of 16 mutations and gene amplification were identified in the KEAP1, NRF2, p62/SQSTM1, HMOX-1, and MOAP1 for both cancer groups, and the mutation carrying frequency was 4.6%. IDH1 p.R132H and NRF2 p.S164* mutation association was determined in 1 patient with LGG. KEAP1, NRF2, and HMOX1 expression levels for both LGG and GBM subtypes were determined to be high in patient samples compared to healthy samples (p<0.05). Conclusion: By targeting the NRF2/KEAP1/p62/SQSTM1 pathway anomalies, new therapeutic approaches can be provided in the treatment of glioma, particularly for chemotherapy sensitivity.Öğe Examination of the relationship between variants in the gene region encoding soluble epoxy hydrolase enzyme hydrolytic activity and type 2 diabetes(Bayrakol Medical Publisher, 2024) Ozmen, Esma; Ayan, Durmus; Onder, Cagatay Emir; Akin, Dilara Fatma; Kose, Burcu; Sari, Ismail; Yazici, CevatAim: Epoxyeicosanoids function as signal mediators in critical biological processes such as platelet aggregation, vasodilation, and anti -inflammation. With all these properties, Epoxyeicosanoids have been associated with many diseases. Metabolism of epoxyeicosanoids is carried out by soluble epoxide hydrolase enzymes, and as a result dihydroxyeicosatrienoic acids, which is a less active form than epoxyeicosanoids, are formed. In our study, SNP/mutation analysis was performed in the gene region responsible for the hydrolase activity of EPHX2, which encodes the soluble epoxide hydrolase enzyme. Material and Methods: The study consisted of two groups: a healthy group with 30 individuals and a T2DM patient group with 40 individuals. SNP/mutation analysis in the gene region responsible for the hydrolase activity of EPHX2 in both groups was performed by Sanger sequencing using appropriate primers. Result: A total of 12 mutations were detected in both groups as a result of Sanger sequencing. Two of the 12 detected mutations were missense mutations (p.Asn359Thr and p.Ser412Arg). It was determined that the pathogenic scores of these mutations were close to 1 for Poly-Phen2 and 0-100 for SNAP. In addition, two (c.1058+165C>T and c.1058+146G>A) SNPs were detected in the intron we observed in the T2DM group, which has not been detected and defined before in our study. Discussion: We believe that the mutations detected in our study, especially those that cause amino acid changes, may cause T2DM susceptibility in healthy individuals and progression of the disease pathogenesis in the T2DM group. We think that the detection of c.1058+165C>T and c.1058+146G>A mutations for the first time in our study will guide the next studies.Öğe In silico analysis of DEL-1 and inflammation-related genes in lung squamous cell carcinoma(Elsevier Gmbh, 2024) Ilikci-Sagkan, Rahsan; Akin, Dilara Fatma; Liman, Recep; Ali, Muhammad MuddassirAim: Twenty to thirty percent of non-small cell lung cancers (NSCLC) are caused by lung squamous cell carcinoma (LUSC), especially in smokers and there has been limited study previously evaluating the situation in terms of the genome and gene expression profile, which demonstrates the relationship among DEL-1, leucocyte recruitment, and pro-inflammatory cytokines in LUSC. Material and methods: In the current study, the m-RNA expression patterns and mutation profiles of our target genes, such as, pro-inflammatory cytokines, chemoattractant molecules, and DEL-1 genes, in 511 LUSC patients. To find the harmful mutations, the PolyPhen-2 and SNAP programs were employed. Not only gene expression was detected, but also survival analysis and correlation between DEL-1 and other target genes' expression levels were explored too. Results: Target genes such as, DEL-1, TNF, IL-18, IL-1, CXCL8, CXCL13, and IL-6 were found to have a total genetic anomaly carrying rate of 16.4%. Seven mutations were found, and two of those mutations have a pathogenic aspect. Deep deletion and gene amplification of the genetic anomalies were also observed. According to gene expression analysis results in the LUSC patient group; DEL-1 and IL-6 levels were significantly lower than those of the control group, whereas the CXCL13 level was found to be higher. Conclusion: Findings of the current study revealed that, there is a significant role of DEL-1 in LUSC pathogenesis. Since present study is an in silico-centered study, this approach can give more insight on experimental studies. These events may support that one of the cancer improvement mechanisms depending on DEL-1 gene at the molecular level.Öğe Molecular profiling of TAM tyrosine kinase receptors and ligands in endometrial carcinoma: An in silico-study(Elsevier Taiwan, 2023) Akin, Dilara Fatma; Ozkan, DidemObjectives: 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.Material and methods: Mutation and expression profiles of the Uterine Corpus Endometrial Carcinoma (UCEC) cohort (n 1/4 509) 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.Results: 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.Conclusion: 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.(c) 2023 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
