Dataset Information

Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target.

ABSTRACT: Transcription factor-7-like-2 (TCF7L2), a vital member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family, plays an important role in normal human physiological and pathological processes. TCF7L2 exhibits multiple anti-atherosclerotic effects through the activation of specific molecular mechanisms, including regulation of metabolic homeostasis, macrophage polarization, and neointimal hyperplasia. A single-nucleotide substitution of TCF7L2, rs7903146, is a genetic high-risk factor for type 2 diabetes and indicates susceptibility to cardiovascular disease as a link between metabolic disorders and atherosclerosis. In this review, we summarize the anti-atherosclerosis effect and novel mechanisms underlying the function of TCF7L2 to elucidate its potential as an anti-atherosclerosis biomarker and provide a novel therapeutic target for cardiovascular diseases.

SUBMITTER: Li J

PROVIDER: S-EPMC8459927 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target.

Li Junyi J Zhou Li L Ouyang Xinping X He Pingping P

Frontiers in cardiovascular medicine 20210909

Transcription factor-7-like-2 (TCF7L2), a vital member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family, plays an important role in normal human physiological and pathological processes. TCF7L2 exhibits multiple anti-atherosclerotic effects through the activation of specific molecular mechanisms, including regulation of metabolic homeostasis, macrophage polarization, and neointimal hyperplasia. A single-nucleotide substitution of TCF7L2, rs7903146, is a genetic high-risk factor for ...[more]

PMID: 34568447

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Project description:BackgroundIncreasing evidence has demonstrated the critical roles of mRNA modification regulators on multiple types of cancers. However, it is still poorly known about the prognostic and therapeutic value of mRNA modification regulators in HNSCC.MethodsThe gene expression profile of 36 mRNA modification regulators and their corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Stepwise regression in R with both directions was used to construct a model for the prognosis of HNSCC. Univariate Cox regression survival analysis was performed to identify the most significant risk gene. Gene set enrichment analysis (GSEA) was applied to determine the cancer-associated pathways with NAT10. Immunohistochemistry (IHC) staining was performed to evaluate the expression of NAT10 in formalin fixed paraffin-embedded (FFPE) samples of HNSCC. Univariate and multivariate Cox regression survival analysis performed to identify the independent risk factors associated with the OS of patients with HNSCC. HNSCC cell lines (Cal-27, FaDu, and Detroit-562) were transfected with short interfering RNA (siRNA) targeting NAT10 or treated with Remodelin, a small-molecule inhibitor of NAT10. Knockdown efficiency of siRNA was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. In addition, CCK-8 assay, scratch assay and transwell assay were used to examine the proliferation, migration, and invasion abilities of the three HNSCC cell lines after NAT10 was inhibited genetically and pharmaceutically. Cell cycle and cell apoptosis assays were performed by flow cytometry. Finally, the therapeutic value of Remodelin in HNSCC was evaluated via a patient-derived xenograft (PDX) model. The statistical analysis was performed with SPSS 23.0.ResultsA risk prediction model containing 10 mRNA modification regulators was constructed and showed prognostic value in HNSCC. NAT10 was further identified as a key risk gene and independent prognostic factor in TCGA HNSCC dataset. The GSEA analysis suggested that high NAT10 expression was associated with MYC, E2F, G2M checkpoint, mTORC1, DNA repair and oxidative phosphorylation pathways. NAT10 protein expression was significantly up-regulated in tumour cells compared to normal epithelial cells in FFPE samples and increased NAT10 protein expression was correlated with poor overall survival of 267 HNSCC patients. Genetic depletion of NAT10 using siRNA or chemical inhibition of NAT10 using Remodelin resulted in reduced cell proliferation, migration and invasion abilities in Cal-27, FaDu and Detroit-562 cells. Knockdown of NAT10 using siRNA significantly increased cell cycle arrest in S/G2-phase. Remodelin significantly inhibited tumour growth and tumour cell proliferation in the PDX model of HNSCC.ConclusionsNAT10 could be a potential prognostic marker and a therapeutic target for HNSCC.

Dataset Information

Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target.

Publications

Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target.

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