炎症反应通过STAT3调控miR-21在砷所致肝癌中作用及机制研究

Endemic arseniasis and the arsenic pollutions induced by industry and agriculture damage severely human health.Epidemiological evidences have shown that the exposure to arsenical induces many kinds of cancer, including skin cancer, lung cancer and hepatoma, howerve, their molecular mechanisms remain unclear.Many studies have shown that there is a close relationship between chronic inflammation and tumorigenesis. The roles and mechanisms of proinflammatory cytokines-regulated miRNA in carcinogenesis induced by environmental carcinogens remain largely investigated. Based on our preliminary results that arsenic induced the increases of interleukin-6 (IL-6) level during arsenite-induced transformation of human liver epithelial (THLE-3) cells, we are going to investigate the roles and mechinasms of inflammatory reaction-regulated miR-21 via signal transducer and activator of transcription 3 (STAT3) in arsenic-induced tumorigenesis of liver and to identify IL-6, STAT3 and miR-21 as novel molecular markers and therapeutic targets of arsenic carcinogenesis after THLE-3 cells treated by arsenic in the presence or absence of IL-6-neutralizing antibody, WP1066 (STAT3 inhibitor), miR-21-mimic or anti-miR-21, respectively. Our results will be helpful to understand the molecular mechanisms underlying arsenic-induced carcinogenesis of liver, which will provide new clues to find early biomarkers and novel measures of preventing and treating arseniasis.

地方性砷中毒及工农业生产所致砷化物污染严重危害人类健康。长期暴露砷化物可引起皮肤癌、肺癌和肝癌等多种癌症，但其分子机制尚不清楚。慢性炎症与肿瘤发生发展有密切的联系，促炎症细胞因子调控微小RNA（miRNA）在环境致癌物所致肿瘤中的作用及机制研究报道甚少。本项目在已发现亚砷酸钠慢性处理引起肝THLE-3细胞恶性转化过程中存在白介素-6（IL-6）水平升高的研究基础上，分别通过亚砷酸钠单独或联合IL-6中和抗体、信号转导和转录激活因子-3（STAT3）抑制剂WP 1066、正义和反义miR-21处理肝THLE-3细胞，并通过裸鼠致瘤模型验证，从正向和反向探讨炎症反应通过STAT3调控miR-21在砷所致肝癌中作用，IL-6、STAT3和miR-21作为砷致癌作用新兴分子标志及治疗靶标的意义，以揭示砷引起肝癌的部分分子机制，为寻找砷所致危害的早期生物标志和发现新的防治措施提供新线索。

地方性砷中毒及工农业生产所致砷化物污染严重危害人类健康。长期暴露砷化物可引起肝癌和皮肤癌等多种癌症，但其分子机制尚不清楚。慢性炎症与肿瘤发生发展有密切的联系，促炎症细胞因子调控微小RNA（miRNA）在环境致癌物所致肿瘤中的作用及机制研究报道甚少。本项目利用已建立低水平亚砷酸钠慢性处理肝上皮L-02细胞和皮肤HaCaT细胞发生上皮间质转化（EMT）和恶性转化细胞模型及亚砷酸钠急性处理所致肝上皮L-02细胞损害模型。运用多种分子生物学和毒理学方法，发现IL-6/STAT3通过调控miR-21在亚砷酸钠慢性处理所致肝细胞和皮肤细胞发生EMT和恶性转化过程中发挥重要作用；MALAT1通过HIF-1α调控糖酵解在亚砷酸钠所致肝细胞损害中具有重要作用和miR-21通过PTEN激活ERK参与亚砷酸钠所致肝细胞自噬过程。获得的研究结果部分揭示了砷暴露所致肝和皮肤组织损达和肿瘤发生发展的部分分子机制，并为寻找砷所致危害的早期生物标志和发现新的防治措施提供新线索。本项目已发表SCI论文4篇（均标注该项目）。本项目的研究结果不仅对于地方性砷中毒而且对于环境砷暴露所致机体损害的防控具有重要科学意义和一定应用价值。