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.

长期接触无机砷的人会诱导肺，皮肤，膀胱和肝癌。分子 砷引起的癌变的机制仍有待阐明。我们的初步研究表明 长期暴露于砷会通过miR-370抑制诱导EGFR，从而激活PKM2和NF-κB。和 通过下调miR-199a表达和NRF2过表达，诱导PKM2表达。 HIF-1α也是 MiR-199a的直接目标。 PKM2与p65和HIF-1α相互作用，激活NF-κB和HIF-1信号。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CXCL8和CXCL5（PKM2的下游效应）激活血管生成。我们已经建立了 一种新型的嵌合肿瘤模型，研究了AS-T细胞和人内皮中信号分子的串扰 调节肿瘤血管生成的细胞。我们假设砷通过miR-370诱导PKM2表达 /miR-199a抑制和NRF2上调，用于诱导细胞转化，肿瘤生长和血管生成。 为了检验这一假设，提出了三个目标：AIM 1将研究PKM2激活的机制和 砷处理引起的上调，并确定PKM2在致癌信号通路中的作用。 AIM 2将研究PKM2途径在砷诱导的细胞转化中的作用和机制 肿瘤生长。 AIM 3将研究PKM2在介导AS-T细胞相互作用中的作用和机制 和内皮细胞以及调节肿瘤血管生成。这个K02将有助于培养候选人的能力 通过为她提供受保护的时间以充分参与职业而实现这些研究目标 发展成为环境健康科学领域的优秀独立研究者 （EHS）。她已经获得了美国癌症协会研究学者的赠款，以调查角色和 CR（VI）诱导的致癌机制以及miRNA（例如miR-143和细胞因子）是否是否 IL-6可以用作早期检测和预防慢性CR（VI）暴露相关的生物标志物 使用人群研究的健康影响。这个K02还将使她专注于研究的新机制 通过PKM2信号通路，砷在诱导的肿瘤发生。她的职业发展计划涉及 在金属相关的癌变中进行技术和分析的激烈培训，这将增强她的知识 和该领域的技能。 K02将具有至关重要的价值，以扩大候选人的研究计划 可能发现砷癌发生的新型机制，这可能为预防慢性的方式铺平了道路 通过中断新型信号通路来引起砷暴露引起的癌变。