New Mechanism of Arsenic Carcinogenesis

人类长期接触无机砷会导致肺癌、皮肤癌、膀胱癌和肝癌。分子 砷的致癌机制尚不清楚。我们的初步研究表明 长期暴露于砷可通过抑制miR-370，激活PKM2和NF-κB，从而诱导表皮生长因子受体； 通过下调miR-199a表达和Nrf2过表达来诱导PKM2的表达。缺氧诱导因子-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(AS-T)肺上皮细胞在体内形成肿瘤并分泌 PKM2的下游效应因子CXCL8和CXCL5可激活血管生成。我们已经确立了 一种新的研究AS-T细胞和人内皮细胞信号分子串扰的嵌合肿瘤模型 细胞在调节肿瘤血管生成中的作用。我们假设砷通过miR-370诱导PKM2的表达 /miR-199a抑制和上调Nrf2诱导细胞转化、肿瘤生长和血管生成。 为了验证这一假说，提出了三个目标：目标1将研究PKM2激活的机制和 砷诱导的细胞表达上调，并确定PKM2在致癌信号通路中的作用。 目的2探讨PKM2通路在砷诱导的细胞转化中的作用及机制。 肿瘤生长。目的3研究PKM2在调节AS-T细胞相互作用中的作用和机制 和血管内皮细胞，并在调节肿瘤血管生成。这个K02将帮助培养应聘者的能力 通过为她提供有保障的时间来完全投入到她的职业生涯中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调查者 (EHS)。她已经获得了美国癌症协会研究奖学金，以调查这一角色 铬(VI)致癌的机制以及miR-143等miRNAs和细胞因子 IL-6可作为早期发现和预防慢性铬(VI)暴露相关不良反应的生物标志物 人口研究对健康的影响。这一K02也将使她专注于研究新的机制 砷通过PKM2信号通路诱导肿瘤发生。她的职业发展计划包括 金属相关致癌技术和分析方面的强化培训，这将增加她的知识 以及这方面的技能。K02将对扩展候选人的研究计划具有关键价值 可能发现砷致癌的新机制，为预防慢性疾病铺平道路 砷暴露通过阻断新的信号通路而致癌。

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.