miR-590协同致癌性KRAS促进肺上皮细胞恶性转化的生物学作用与分子机制

Malignant transformation of normal cells to tumor cells is the initial step of carcinogenesis. Oncogenic activation of mutant KRas, which occurs in as high as 35% cases of lung adenocarcinoma, plays a key role in the process of malignant transformation. However, Oncogenic KRas requires to cooperate with other oncogenes or inactive tumor suppressors to accomplish malignant transformation. Recently, our preliminary results demonstrated that miR-590 was aberrantly upregulated in lung cancer tissues of K-rasV12 transgenic mice. Moreover, miR-590 promoted malignant transformation of immortalized normallung epithelial cells via cooperation with oncogenic KRasV12, resulting in acquired remarkable tumorigenecity in nude mice. At the molecular level, miR-590-5p reduced expression of BTG2 and SPRY2, which functions as negative regulators of Ras signaling, and miR-590-3p reduced expression of tumor suppressor Rb and GSK3β, which respectively, are inhibitors of E2F signaling and β-catenin signaling. Furthermore, we found that several inflammatory cytokines were able to induce miR-590 expression. Therefore, in the current project, we are aiming to systematically investigate the important cooperative role of miR-590-5p/3p, through simultaneously activating Ras/MEK/ERK，Rb/E2F nd GSK3β/β-catenin signaling pathways, with oncogenic KRasV12 in inducing malignant transformation of normal lung epithelial cells, which would shed bright light on the important events during lung carcinogenesis and provide novel therapeutic targets for NSCLC treatment.

正常细胞变成肿瘤细胞的恶性转化是肿瘤发生的前提。癌基因KRas的突变激活是引起恶性转化的重要因素，见于高达35%的肺腺癌。但是致癌性KRas需要协同其它癌基因或失活的抑癌基因才能完成细胞转化。前期我们发现miR-590在KrasV12转基因小鼠形成的肺部肿瘤组织中异常升高。而且miR-590协同激活突变型KRasV12促进肺上皮细胞发生恶性转化，使其在裸鼠体内具有较强的成瘤能力。分子水平上，miR-590-5p下调Ras的负调控蛋白SPRY2和BTG2，miR-590-3p下调抑癌基因Rb和GSK3β的表达；而多种炎症因子上调miR-590的表达。以此为基础，本项目将系统性研究miR-590-5p/3p介导Ras/MEK/ERK，Rb/E2F和GSK3β/β-catenin通路，协同KRasV12促进肺上皮细胞发生恶性转化的重要作用,从而阐明肺癌发生过程中的重大事件，为治疗肺癌提供新靶点

由于对肺癌发生的机制缺乏充分了解，肺癌的诊断一直缺乏重要的预警分子。而目前手术、放疗及化疗等常规治疗技术的治疗结果尚难以令人满意。因此，揭示肺癌发生发展过程中的重大事件，阐明肺癌发生发展的分子机制，是目前肺癌研究中非常迫切的任务。本项目的研究阐明了阻断β-catenin降解、衰老相关炎症的抑癌效应以及细胞自噬等生物学过程可以逃逸致癌性Ras引起的细胞衰老并促进恶性转化，发现了miR-199a和miR-590分子分别阻断β-catenin降解和细胞自噬在致癌性Ras启动肺癌发生的过程中发挥协同作用，探索了拮抗miR-199a或β-catenin转录激活活性具有治疗Ras突变型肺癌的治疗潜能，揭示了在肿瘤发生过程中衰老诱导的炎症现象在衰老逃逸过程中可转化为非可控炎症，参与肺癌的发生发展。