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会诱发肺癌、皮肤癌、膀胱癌和肝癌。 我们的初步研究表明，砷诱发的致癌机制仍有待阐明。 长期接触砷会通过抑制 miR-370 诱导 EGFR，从而激活 PKM2 和 NF-κB； 通过下调 miR-199a 表达来诱导 PKM2 表达，并且 Nrf2 也过度表达。 miR-199a 的直接靶标与 p65 和 HIF-1α 相互作用，激活 NF-κB 和 HIF-1 信号传导。 进一步证明砷转化（As-T）肺上皮细胞在体内形成肿瘤并分泌 我们已经确定，PKM2 的下游效应因子 CXCL8 和 CXCL5 可以激活血管生成。 一种新型嵌合肿瘤模型，用于研究 As-T 细胞和人内皮细胞中信号分子的串扰 我们勇敢地说砷通过 miR-370 诱导 PKM2 表达。 /miR-199a 抑制和 Nrf2 上调可诱导细胞转化、肿瘤生长和血管生成。 为了检验这一假设，提出了三个目标： 目标 1 将研究 PKM2 激活的机制和 砷处理诱导的上调，并确定 PKM2 在致癌信号通路中的作用。 目标2将研究PKM2通路在砷诱导的细胞转化和细胞转化中的作用和机制。 目标 3 将研究 PKM2 在介导 As-T 细胞相互作用中的作用和机制。 该 K02 将有助于培养候选者的能力。 通过为她提供受保护的时间来充分从事她的职业生涯来实现这些研究目标 发展成为环境健康科学领域优秀的独立研究者 （EHS）。她已获得美国癌症协会研究学者资助以研究其作用和 Cr(VI) 诱导癌变的机制以及 miR-143 等 miRNA 和 IL-6 可用作早期检测和预防慢性 Cr(VI) 暴露相关不良反应的生物标志物 这项 K02 还将使她能够专注于研究新的机制。 砷通过 PKM2 信号通路诱导肿瘤发生 她的职业发展计划涉及。 金属相关致癌技术和分析方面的强化培训，这将增强她的知识 K02 对于扩展候选人的研究项目具有重要价值。 发现砷致癌的新机制的潜力可能为预防慢性疾病铺平道路 砷暴露通过中断新的信号通路而导致致癌。