基于miR-130b/MEOX2/Akt信号通路探讨维药骆驼蓬中生物碱类调节结肠癌自噬及转移作用机制

Colorectal cancer is one of the most commonly diagnosed cancers with high degree of migration; there is currently no effective treatment. Peganum Harmala L. (PHL) which is commonly used medicine in Uyghur medicine possesses qusanhanshi, xiaozhongjiedu effect and is clearly used to treat colorectal cancer in clinical, but the material basis and molecular mechanism of action are not clear. In our previous studies, alkaloids compounds from PHL were isolated and identified. It was found that administration of Harmaline can decrease miR-130b and p-Akt, and increase MEOX2 expression levels, promote autophagy, inhibit cell proliferation and migration in human colorectal cancer cells. We also found that overexpression miR-130b could markedly block Harmaline-regulated anti-cancer activity and MEOX2 expression level. This project intends to systematically investigate the chemical constituents from PHL, test anti-proliferation effect, evaluate their pharmacodynamics in vivo and in vitro, and clarify the various potential molecular mechanisms of anti-cancer activity. We will explore the anti-tumor efficacy of PHL; the scientific hypothecs that PHL could regulate autophagy and migration in human colorectal cancer cells by miR-130b/MEOX2/Akt pathways to exert the effect on the anti-cancer joints were verified. The aim of this project is to clarity the material basis, autophagy and migration mechanisms of Uyghur medicine PHL and to provide adequate scientific basis for molecular targeted drug research and its clinical treatment.

结肠癌是常见的恶性肿瘤之一，易于转移，目前尚无理想治疗药物。骆驼蓬是维吾尔医学常用药，具有祛散寒湿、消肿解毒之功效。骆驼蓬临床疗效确切，但物质基础及作用机理尚不清晰。本课题前期研究发现骆驼蓬中的骆驼蓬碱可以降低结肠癌细胞中miR-130b和p-Akt的表达，上调MEOX2的表达，并具有诱导自噬、抑制增殖及转移的活性。同时，研究发现过表达miR-130b可以显著阻断骆驼蓬碱的抗结肠癌作用和对MEOX2的调节；本项目拟对骆驼蓬中生物碱类进行系统的化学成分研究，通过活性筛选及体内、外药效评价，明确其活性成分，阐明其抗结肠癌作用机制，探讨骆驼蓬抗结肠癌药效物质基础，验证“骆驼蓬中生物碱类调节miR-130b/ MEOX2/Akt轴影响结肠癌细胞自噬及其转移分子机制发挥抗肿瘤作用”科学假说。本研究拟阐明维药骆驼蓬抗结肠癌的药效物质及作用机制，为临床用药及抗结肠癌分子靶向药物的研发提供科学依据。

结肠癌是常见的恶性肿瘤之一，其治疗是一个棘手的问题，目前尚无理想治疗药物。维药骆驼蓬具有祛散寒湿、消肿解毒、镇咳止喘、解郁补脑等功效。本课题围绕维药骆驼蓬中主要活性成分进行系统的化学成分研究，分离得到15个化合物，并鉴定了其化学结构。通过体外活性筛选及体内外药效学评价，发现骆驼蓬碱和去甲骆驼蓬碱具有较好的抗结肠癌活性。利用多种细胞生物学、分子生物学手段，结合现代科学技术方法，明确其分子作用机理，为抗肿瘤小分子药物的研发提供实验基础。以第一或通讯作者发表科研论文13篇，其中SCI论文10篇；申请发明专利3项，培养研究生6人，入选国家“万人计划”青年拔尖人才、中华中医药学会“中青年创新人才”、天津市“中青年科技创新领军人才”、天津市高校“中青年骨干创新人才培养计划”、天津市特聘教授“青年学者”等。