MELK作为肺癌潜在治疗靶点的研究及其抑制剂筛选

Lung cancer has been the fastest increasing rate of morbidity and mortality in global, threatening the human health. In china, the morbidity and mortality of lung cancer top the malignant tumor’s ranking, and most patients are diagnosed at the advanced stages. As the main therapy of advanced lung cancer, chemotherapeutics still stagnate in recently 10 years. Moreover, there are few targeted drugs applied in curing lung cancer in clinic. Thus, it is urgent to search novel target to lung cancer and design the target’s associated drugs. Our bioinformatics analyses and experimental data showed that the elevated level of MELK was observed in lung cancer patients, which was strongly correlated with reduced overall survival; overexpression of MELK also promoted the tumor cell proliferation, invasion, metastasis, and clone formation. Based on these results, we propose MELK as a potential therapeutic target of lung cancer and the application of its inhibitors could be effective drugs for the treatment of lung cancer. In this study, we will investigate the functions, mechanisms and epigenetic regulation of MELK to confirm that it is a potential therapeutic target of lung cancer. Furthermore, we will identify inhibitors targeting MELK using virtual screening followed by high throughput drug screening. It is necessary and important to identify MELK as a potential drug target and guide the treatment of lung cancer in clinic.

在全球范围内，肺癌已成为发病率和死亡率增长最快的恶性肿瘤之一，严重威胁着人类的健康。在我国，肺癌的发病率和死亡率高居恶性肿瘤首位，且多数患者确诊时已属晚期。而化疗作为肺癌晚期治疗的主要手段，在近十年来并未有突破性进展, 且可有效用于临床治疗肺癌的靶向药物依旧稀少。因此，寻求新的肺癌治疗靶标并以此获得高效低毒的新靶向药物，依旧是一项充满挑战且极为迫切的任务。我们的生物信息学分析和实验数据显示MELK在肺癌中高表达，并与患者的低生存率密切相关；过表达MELK促进肿瘤细胞增殖、侵袭、转移和克隆形成。因此，我们认为MELK是肺癌潜在治疗靶点，其抑制剂是治疗肺癌的有效药物。本研究将从MELK的功能、作用机制和表观遗传调控三个方面确认MELK为肺癌潜在治疗靶点，并采用虚拟筛选结合高通量筛选模型筛选药效高、特异性强的MELK抑制剂。本课题的研究对确立MELK为肺癌药物靶点及肺癌的临床治疗具有指导意义

作为全球发病率和死亡率增长最快的恶性肿瘤之一，肺癌严重威胁人类的健康。在我国，肺癌的发病率与死亡率高居恶性肿瘤的首位，且多数患者确诊时已属晚期。而化疗作为肺癌晚期治疗的主要手段，在近十年来并未有突破性进展，且可有效用于临床治疗肺癌的靶向药物依旧稀少。因此，寻求新的肺癌治疗靶标并以此获得高效低毒的新靶向药物，则迫在眉睫。本研究首先通过生物信息学发现MELK杂肺癌中高表达，且与肺癌的生存率成负相关。肺癌组织芯片的免疫结果也表明MELK在肺癌组织中高表达。其次，体内和体外实验证明，过表达MELK可以促进肺癌细胞的生长、迁移和侵袭。最后，构建了MELK在肺癌中的调控网络，证实MELK可以通Twist1、Slug、MMP7、E-cadherin和N-cadherin调控肺癌的迁移和侵袭，借由PLK1-CDC25C-CDK1途径参与G2/M期的调控，抑制MELK的活性可以诱发凋亡介导的焦亡。以上研究表明MELK是肺癌治疗的重要靶点。另外，本研究构建了MELK在增殖、转移和死亡中的调控网络，为肺癌抑制剂的设计提供新的思路，并为这些抑制剂将来的应用或者和其他药物的联用提供新的切入点。而且，本研究通过筛选得到特异性好、亲和力强的MELK抑制剂，并建立了MELK抑制剂的高通量筛选模型，为后期的进一步开发提供了坚实的基础。

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