Translational Control in Cr(VI) Carcinogenesis

Cr(VI) 致癌过程中的转化控制

• 批准号: 10194498
• 负责人: QING-BAI SHE
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194498
• 关键词: Appalachian Region; Biochemical; Biology; Cancer Etiology; Cessation of life; Chronic; Clinical; Development; Dose; EIF4EBP1 gene; EZH2 gene; Environment; Environmental Carcinogens; Environmental Pollutants; Epithelial Cells; Eukaryotic Initiation Factor-4F; Exposure to; FRAP1 gene; Fostering; Gene Expression; Genes; Genetic Transcription; Genetic Translation; Genetically Engineered Mouse; Growth; Histone-Lysine N-Methyltransferase; Human; In Vitro; Incidence; Injury; Kentucky; Knockout Mice; Lung; Lung Inflammation; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; Metals; Molecular; Molecular Analysis; Molecular Target; Mus; Occupational; Oncologist; Oncoproteins; Outcome Study; Particulate; Pathologist; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Polyribosomes; Positioning Attribute; Post-Transcriptional Regulation; Prevention; Prevention strategy; Preventive therapy; Process; Property; Protein Biosynthesis; Proteins; Public Health; Research; Ribosomes; Role; Scheme; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic Intervention; Translating; Translation Initiation; Translational Activation; Translational Regulation; Translations; Tumorigenicity; Up-Regulation; Wild Type Mouse; Work; base; bronchial epithelium; cancer stem cell; carcinogenesis; carcinogenicity; cell growth; cell transformation; cell type; chromium hexavalent ion; clinically relevant; effectiveness evaluation; experience; genetic approach; improved; inhibitor/antagonist; innovation; insight; mRNA capping; mTOR inhibition; migration; novel; pollutant; polysome profiling; recruit; response; stem-like cell; targeted biomarker; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis; uncontrolled cell growth

PROJECT SUMMARY Cr(VI) is a common and well-recognized environmental carcinogen that causes lung and other cancers in human. Despite considerable research effort to understand the molecular and cellular mechanisms of Cr(VI) carcinogenesis, crucial facets of these mechanisms remain largely unknown; identification of the key molecular regulators and processes, the mechanisms of action, and strategies for prevention are urgently needed. Remarkable progress has been made that highlights the functional importance of mRNA translation and protein synthesis in cancer development and progression. However, translational control of Cr(VI) carcinogenesis has not yet been investigated. We recently demonstrated that chronic low dose Cr(VI) exposure in human lung bronchial epithelial cells can induce cancer stem cell (CSC)-like properties, cell transformation and tumor formation through upregulation of histone-lysine methyltransferases including G9a, SUV39H1 and EZH2. Notably, we found that chronic Cr(VI) exposure can activate mTOR kinase leading to phosphorylation (inactivation) of the translational repressor 4E-BP1, and thereby promote the recruitment of capping mRNAs and ribosomal subunits to the eIF4F translation initiation complex (eIF4E+eIF4G+eIF4A) for active translation in polysomes. Furthermore, we found that on chronic Cr(VI) exposure, the EZH2 mRNA is actively translated in polysomes with no changes in its transcriptional level. Importantly, targeted inhibition of mTOR kinase can inhibit translation of EZH2 mRNA in polysomes and result in growth inhibition of Cr(VI)-transformed cells. Based on these findings, the central hypothesis of the proposed study is that the activation of cap-dependent mRNA translation machinery by mTOR kinase is required to selectively upregulate key oncoproteins that confer Cr(VI)- induced tumorigenesis. To test this hypothesis, two specific aims are proposed. Aim 1 will define the role of mTOR-activated translation machinery in Cr(VI)-induced tumorigenesis using a combination of molecular, cellular, biochemical, and pharmacologic approaches, as well as genetically engineered mouse models with clinical association schemes. Aim 2 will characterize the molecular mechanism of mTOR-activated cap- dependent translation in Cr(VI) carcinogenicity using a polysome profiling approach to systematically identify a set of key mRNAs that are selectively recruited to polysomes and translated in Cr(VI)-transformed human bronchial epithelial cells, followed by characterization of their functional importance in Cr(VI)-induced tumorigenicity. Our proposed study will investigate the innovative concept that Cr(VI) induces carcinogenesis through dysregulation of the mTOR/4E-BP1-mediated translation initiation process. Elucidating this process will provide novel insights into the biology and clinical relevance of translational regulation in Cr(VI) carcinogenesis. This research will have the added benefit of identifying Cr(VI)-induced translationally-regulated targets for potential preventive or interventional therapy.

项目总结 铬(VI)是一种常见的、公认的环境致癌物，可引起人类的肺癌和其他癌症。 尽管人们对铬(VI)的分子和细胞机制进行了大量的研究 致癌，这些机制的关键方面在很大程度上仍不清楚；关键分子的鉴定 迫切需要监管机构和程序、行动机制和预防战略。 已经取得了显著的进展，突显了信使核糖核酸翻译和蛋白质的功能重要性 合成与癌症的发生和发展。然而，铬(VI)致癌的翻译控制有 还没有被调查。我们最近证实，慢性低剂量铬(VI)暴露于人肺 支气管上皮细胞可诱导肿瘤干细胞样特性、细胞转化和肿瘤 通过上调组蛋白-赖氨酸甲基转移酶G9a、SUV39H1和EZH2形成。 值得注意的是，我们发现慢性铬(VI)暴露可以激活mTOR激酶，导致磷酸化 (失活)翻译抑制物4E-BP1，从而促进封顶mRNAs的招募，并 EIF4F翻译起始复合体(eIF4E+eIF4G+eIF4A)的核糖体亚基，用于主动翻译 多聚体。此外，我们还发现，在慢性铬(VI)暴露下，EZH2 mRNA被积极地翻译成 多聚体，其转录水平没有变化。重要的是，靶向抑制mTOR激酶可以抑制 EZH2mRNA在多聚体中的翻译并导致铬(VI)转化细胞的生长抑制。基于 这些发现，拟议研究的中心假设是帽依赖的mRNA的激活 MTOR激酶的翻译机制需要选择性地上调关键的癌蛋白，这些癌蛋白提供铬(VI)- 诱导肿瘤形成。为了验证这一假设，本文提出了两个具体目标。目标1将定义 MTOR激活的翻译机制在铬(VI)诱导的肿瘤发生中使用的分子， 细胞、生化和药理学方法，以及基因工程小鼠模型 临床联合方案。目的2研究mTOR激活的CaP-2的分子机制。 用多聚体谱方法系统地鉴定铬(VI)致癌性中的依赖翻译 选择性地招募到多聚体并在铬(VI)转化的人中翻译的一组关键mRNAs 支气管上皮细胞及其在铬(VI)诱导中的功能重要性 致瘤性。我们建议的研究将探索铬(VI)诱导致癌的创新概念 通过mTOR/4E-BP1介导的翻译启动过程的失调。阐明这一过程将会 为翻译调控在铬(VI)致癌中的生物学和临床相关性提供新的见解。 这项研究将有额外的好处，识别铬(VI)诱导的翻译调控靶标 潜在的预防性或介入性治疗。