New Mechanism of Arsenic Carcinogenesis

砷致癌的新机制

• 批准号: 10301856
• 负责人: Ling-Zhi Liu
• 金额: $ 10.77万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-13 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301856
• 关键词: New; Mechanism; Arsenic; Carcinogenesis

Long-term human exposure to inorganic arsenic induces lung, skin, bladder and liver cancer. The molecular mechanisms of arsenic-induced carcinogenesis remain to be elucidated. Our preliminary studies show that long-term exposure to arsenic induces EGFR via miR-370 suppression, which activates PKM2 and NF-κB; and induces PKM2 expression via downregulation of miR-199a expression and Nrf2 overexpression. HIF-1α is also a direct target of miR-199a. PKM2 interacts with p65 and HIF-1α to activate NF-κB and HIF-1 signaling. We further demonstrated that arsenic-transformed (As-T) lung epithelial cells form tumors in vivo and secrete factors CXCL8 and CXCL5, the downstream effectors of PKM2, to activate angiogenesis. We have established a novel chimeric tumor model to study the crosstalk of signaling molecules in As-T cells and human endothelial cells in regulating tumor angiogenesis. We hypothesize that arsenic induces PKM2 expression via miR-370 /miR-199a suppression and Nrf2 upregulation for inducing cell transformation, tumor growth and angiogenesis. To test this hypothesis, three aims are proposed: Aim 1 will investigate the mechanism of PKM2 activation and upregulation induced by arsenic treatment, and determine the role of PKM2 in oncogenic signaling pathway. Aim 2 will investigate the role and mechanism of PKM2 pathway in arsenic-induced cell transformation and tumor growth. Aim 3 will investigate the role and mechanism of PKM2 in mediating interactions of As-T cells and endothelial cells and in regulating tumor angiogenesis. This K02 will help foster the candidate’s ability to achieve these research goals by providing her with protected time to be fully engaged in her career development to become an excellent independent investigator in the field of Environmental Health Science (EHS). She has obtained American Cancer Society Research Scholar Grant to investigate the role and mechanisms of Cr(VI)-induced carcinogenesis and whether miRNAs such as miR-143 and cytokines such as IL-6 can be used as biomarkers for early detection and prevention of chronic Cr(VI) exposure-related adverse health effects using population study. This K02 will also allow her to focus on studying new mechanism of arsenic in inducing tumorigenesis through PKM2 signaling pathway. Her career development plan involves intense training in techniques and analysis in metal-related carcinogenesis, which will enhance her knowledge and skills in this area. The K02 will be of critical value to expand the candidate’s research program with the potential to discover novel mechanisms of arsenic carcinogenesis that may pave the way to prevent chronic arsenic exposure-caused carcinogenesis by interrupting the novel signaling pathway.

人体长期接触无机砷可诱发肺癌、皮肤癌、膀胱癌和肝癌。分子 砷诱导的致癌机制仍有待阐明。我们的初步研究表明， 长期暴露于砷通过miR-370抑制诱导EGFR，其激活PKM 2和NF-κB;和 通过下调miR-199 a表达和Nrf 2过表达诱导PKM 2表达。HIF-1α也是 miR-199 a的直接靶点。PKM 2与p65和HIF-1α相互作用，激活NF-κB和HIF-1信号传导。我们 进一步证明砷转化的（As-T）肺上皮细胞在体内形成肿瘤并分泌 因子CXCL 8和CXCL 5，PKM 2的下游效应物，以激活血管生成。我们建立 研究As-T细胞和人内皮细胞中信号分子串扰的新型嵌合肿瘤模型 细胞调节肿瘤血管生成。我们假设砷通过miR-370诱导PKM 2表达 /miR-199 a抑制和Nrf 2上调用于诱导细胞转化、肿瘤生长和血管生成。 为了验证这一假设，提出了三个目标：目标1将研究PKM 2激活的机制， 上调砷处理诱导，并确定PKM 2在致癌信号通路中的作用。 目的2探讨PKM 2通路在砷诱导的细胞转化中的作用和机制， 肿瘤生长目的3探讨PKM 2在介导As-T细胞相互作用中的作用及机制 和内皮细胞以及调节肿瘤血管生成。此K 02将有助于培养候选人的能力， 通过为她提供受保护的时间来实现这些研究目标，以充分参与她的职业生涯 发展成为环境健康科学领域的优秀独立调查员 （EHS）。她获得了美国癌症协会研究学者资助，以调查这一作用， Cr（VI）诱导的致癌机制以及是否存在miRNAs如miR-143和细胞因子如 IL-6可作为早期检测和预防慢性Cr（VI）缺乏相关不良反应的生物标志物 使用人口研究的健康影响这K 02也将使她能够专注于研究新的机制， 砷通过PKM 2信号通路诱导肿瘤发生。她的职业发展计划包括 在金属相关致癌作用的技术和分析方面的强化培训，这将增强她的知识 这方面的技能。该K 02将是至关重要的价值，以扩大候选人的研究计划与 发现砷致癌新机制的潜力，可能为预防慢性砷中毒铺平道路。 砷通过阻断新的信号通路而导致致癌。