Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity

RNA结合蛋白和T细胞在口腔上皮可塑性中的交叉点

• 批准号: 10178000
• 负责人: Shikhar Mehrotra
• 金额: $ 45.49万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10178000
• 关键词: Binding; Biological; Biology; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell Survival; Collaborations; Cues; Data; Development; Disease; Down-Regulation; Elements; Embryo; Energy Metabolism; Epithelial; Epithelial Cells; Equilibrium; Eukaryota; Exhibits; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Glycolysis; Head and Neck Squamous Cell Carcinoma; Health; Homeostasis; HuR protein; Human; Hyperplasia; IL2RA gene; Immune; Immune response; Immunosuppression; Inflammation; Interferon Type II; Intervention Studies; Keratin; Knock-out; Knockout Mice; Laboratories; Lead; Lesion; Mammalian Cell; Mass Spectrum Analysis; Mediating; Messenger RNA; Metabolic; Modeling; Molecular; Mouth Neoplasms; Mus; Nitroquinolines; Oral; Outcome; Oxidative Phosphorylation; Oxides; Pathologic; Pharmaceutical Preparations; Pharmacology; Play; Positioning Attribute; Post-Transcriptional Regulation; Property; Proteins; Proteomics; Publishing; Pyrvinium pamoate; RNA; RNA-Binding Proteins; Regulator Genes; Regulatory T-Lymphocyte; Resistance; Role; Spleen; Squamous cell carcinoma; T cell response; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Organisms; Translations; Tumor Tissue; Tumor-infiltrating immune cells; Vision; anti-tumor immune response; bench to bedside; carcinogenesis; cell mediated immune response; cytokine; effector T cell; experimental study; glucose metabolism; insight; malignant mouth neoplasm; mouse model; mouth squamous cell carcinoma; neoplastic cell; novel; oral cavity epithelium; oral tumorigenesis; overexpression; prevent; response; small molecule; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumor immunology; tumor metabolism; tumor microenvironment; tumor progression; tumorigenesis

ABSTRACT RNA-binding proteins (RBPs) are critical regulators of gene expression in eukaryotes. However, the contribution of RBPs in oral epithelial homeostasis and oral pathological diseases remain mostly elusive. Our recent efforts demonstrate that dysregulated RBP HuR (Hu-Antigen R) disintegrate oral epithelium and contribute to oral tumorigenesis. HuR can bind AU-rich elements of mRNA sequences and regulates its stability of translation. Our preliminary data revealed that HuR binds and controls the expression of a subset of mRNAs encoding proteins involved in glucose metabolism. In collaboration with the Mehrotra group we show that epithelial specific HuR cross talk with immune response and contribute to oral tumorigenesis. Using T-cell immune plasticity functions, we plan to study the functional properties of HuR in oral epithelial and T-cells for anti-tumor activity. Here, we demonstrated that epithelial-specific HuR knockout modulates the epithelial homeostasis and oral tumorigenesis, whereas HuR KO T cells exhibit enhanced IFNγ secretion by regulating glucose metabolism that alters the balance between the immunosuppressive regulatory T cells (Treg's) and effector T cells. While the oral epithelial alterations by HuR likely reflects the metabolic cues from T-cells, a major unanswered question pertains to the mechanism of HuR in human oral cancer where there are immune suppression and metabolic reprogramming. Collectively, HuR targets glucose metabolism genes in the oral epithelium and its involvement in T-cell specific immune plasticity stimulated a coalescence of efforts from the Palanisamy and Mehrotra groups to elucidate the underlying mechanisms of HuR and oral tumorigenesis, and T-cell mediated immune plasticity, respectively. The overarching hypothesis is that HuR-mediates gene regulation and cross-talk between oral epithelial and immune T cells compartments by a novel mechanism, and silencing HuR associated gene network is critical for epithelial and metabolic reprogramming to limit oral cancer progression. The outcome of our studies will result in advanced therapeutic intervention studies and translation from bench to bedside.

摘要 RNA结合蛋白（RBP）是真核生物基因表达的重要调控因子。然而，在这方面， RBP在口腔上皮稳态和口腔病理疾病中作用仍然存在 大多是难以捉摸的我们最近的努力表明，失调的RBP HuR（Hu-Antigen R） 使口腔上皮崩解并促进口腔肿瘤发生。HuR可以结合富含AU的元素 mRNA序列，并调节其翻译的稳定性。我们的初步数据显示， HuR结合并控制编码蛋白质的mRNA亚组的表达，所述蛋白质涉及 葡萄糖代谢与Mehrotra小组合作，我们发现上皮特异性HuR 与免疫应答相互作用并促进口腔肿瘤的发生。利用T细胞免疫 可塑性功能，我们计划研究口腔上皮细胞和T细胞中HuR的功能特性 用于抗肿瘤活性。在这里，我们证明了上皮特异性HuR敲除调节了 上皮稳态和口腔肿瘤发生，而HuR KO T细胞表现出增强的 IFNγ分泌通过调节葡萄糖代谢，改变 免疫抑制调节性T细胞（Treg）和效应T细胞。而口腔上皮细胞 HuR的改变可能反映了T细胞的代谢线索，这是一个尚未回答的主要问题。 涉及存在免疫抑制的人类口腔癌中HuR的机制 和代谢重编程总的来说，HuR靶向口腔中的葡萄糖代谢基因， 上皮及其参与T细胞特异性免疫可塑性刺激了 Palanisamy和Mehrotra小组努力阐明HuR的潜在机制， 和口腔肿瘤发生，和T细胞介导的免疫可塑性，分别。总体 假设HuR介导基因调节和口腔上皮与 免疫T细胞隔室通过一种新的机制，并沉默HuR相关基因 网络对于上皮和代谢重编程以限制口腔癌进展至关重要。的 我们的研究结果将导致先进的治疗干预研究和翻译 从长凳到床边