METTL3 in chromium-induced angiogenesis and carcinogenesis

METTL3 在铬诱导的血管生成和癌变中的作用

• 批准号: 10615806
• 负责人: STEVEN B. MCMAHON
• 金额: $ 51.95万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-29 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615806
• 关键词: Adenosine; Animal Model; Biological Assay; Biological Markers; Blood; Blood specimen; CRISPR/Cas technology; CXCL5 gene; Cell Proliferation; Cells; Chromates; Chromium; Chronic; Development; Dose; Endothelial Cells; Environmental Carcinogens; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial Cells; Exposure to; Future; Gene Chips; Goals; Hypoxia Inducible Factor; IL8 gene; IL8RA gene; Interleukin 8A Receptor; Knock-out; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; Metal exposure; Methylation; Methyltransferase; Modeling; Modification; Molecular; Mononuclear; Mus; Occupational Exposure; Peripheral Blood Mononuclear Cell; Play; RNA; RNA Interference; Role; SOX4 gene; Sampling; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Techniques; Testing; Tissue Sample; Tube; Tumor Angiogenesis; Up-Regulation; Vascular Endothelial Cell; angiogenesis; cancer prevention; cancer type; carcinogenesis; cell transformation; chemokine; chromium hexavalent ion; disorder prevention; early detection biomarkers; epidemiology study; exposed human population; human subject; hypoxia inducible factor 1; interest; non-smoking; novel; overexpression; paracrine; posttranscriptional; receptor; transcription factor; tumor; tumor growth; tumorigenesis; whole genome

Exposure of hexavalent chromium [Cr(VI)] is known to induce lung cancer. Although there is emerging interest in mechanisms of Cr(VI)-induced carcinogenesis, role of Cr(VI) in inducing RNA modification in carcinogenesis is unknown. Our preliminary studies found that higher levels of methyltransferase like 3 (METTL3) were found in lung tissues from Cr(VI)-exposed mice, samples from Cr(VI)-exposed nonsmoking workers, and Cr(VI)- transformed (Cr-T) cells. To study underlying mechanism, we found that METTL3 was induced by upregulation of Nrf2 and SOX4, two important transcription factors. We found that METTL3 was important in regulating Cr-T cell proliferation, tube formation and tumor angiogenesis. METTL3 induced hypoxia-inducible factor 1 (HIF- 1) expression through suppressing PHD2, suggesting METTL3/PHD2/HIF-1 signaling would be important in Cr(VI) carcinogenesis. C-X-C motif chemokine 5 (CXCL5) and IL-8 were downstream effectors of METTL3. Our whole genome expression array analysis of blood mononuclear cells (PBMCs) from Cr(VI)-exposed nonsmoking workers and control subjects showed that METTL3, CXCL5 and IL-8 were among the most upregulated molecules in Cr(VI) exposure group, which was validated using RT-qPCR and ELISA assays. We hypothesize that long-term Cr(VI) exposure induces METTLE3 overexpression to regulate cell transformation, tumor growth and angiogenesis through METTL3/PHD2/HIF-1 axis in lung epithelial cells, and SOX4 and NRF-2 are two key upstream inducers. In order to test this hypothesis, we will perform three specific aims: Aim 1) To determine role and mechanism of METTL3 upregulation in Cr(VI)-induced cell transformation, tumor growth and angiogenesis, and to identify upstream regulator(s) of METTL3 elevation in Cr-T cells. Aim 2) To investigate key downstream targets and molecules of METTL3 in Cr(VI)-induced cell transformation and tumor growth. Aim 3) To determine whether METTL3 upregulation in Cr-T cells induces tumor angiogenesis through CXCR1/2 receptors and paracrine effect using humanized chimeric tumor model; to determine expression levels of Nrf2, SOX4, METTL3, PHD2, HIF-1, CXCL5, and/or IL-8 in peripheral blood mononuclear cells (PBMCs) and lung tissues from the Cr(VI)-exposed mice and in PBMCs from workers with occupational exposure to Cr(VI). We will use a combination of molecular approaches, animal models, and blood and tissue samples from human subjects and mice to define the role and mechanisms of new METTL3/PDH2/HIF-1 axis induced by Nrf2 and SOX4 in mediating cell transformation, tumor growth and angiogenesis, and determine the possible correlations with Cr(VI) internal exposure doses in workers and in mice via levels of these molecules. We will also investigate the effects of downstream effectors of METTL3/PDH2/HIF-1 axis, and their receptors in Cr-T cell-inducing angiogenesis. These studies will help us understand underlying mechanisms of Cr(VI) in inducing tumor growth and angiogenesis, and identify new biomarkers for early detection of Cr(VI) exposure and cancer prevention.

已知暴露于六价铬[Cr(VI)]可诱发肺癌。尽管人们越来越感兴趣