蝎毒多肽提取物靶向DLL4/Notch1通路抑制非小细胞肺癌干细胞作用 及关键机制研究

Non-small cell lung cancer (NSCLC) is now regarded as the most common cause of cancer-related mortality in China. Despite continuous efforts to improve the therapeutic response, the overall five-year survival rate for NSCLC is still less than 15%. Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy.Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We hypothesized that targeting cancer stem cells and the tumor vasculature by interfering with the DLL4/Notch1 pathway will improve treatment outcome. We developed Polypeptide extracted from scorpion venom (PESV), a certain group of polypeptide of 50-60 amino acids extracted from Crude venom of BmK with bioactivities, that can inbibit the anigogenesis maturition during the interval of chemotherapy by decreasing the expression of Dll4 and Notch1 in tumor microenvironment. In the present study, we try to study the effect of PESV targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch1 signaling for Non-small cell lung cancer treatment.

肿瘤干细胞在非小细胞肺癌复发、转移中起关键作用，针对肿瘤干细胞异常信号通路进行靶向治疗成为肿瘤治疗的研究热点。传统中药具有多靶点、多环节抗肿瘤的作用优势，在抗肿瘤干细胞药物开发中独具优势。DLL4/Notch1通路不但在肿瘤血管生成中而且在肿瘤干细胞自我更新中发挥重要作用。若以此通路为干预靶点，不但可直接抑制肿瘤干细胞，还可通过抑制其血管微环境间接抑制肿瘤干细胞。研究表明，蝎毒多肽提取物(PESV)兼具多靶点、多环节抑制肿瘤生长转移的特点，但其对肿瘤干细胞作用目前尚无研究报道。本项目拟通过体内、外试验，采用RNA干扰、激光共聚焦、免疫磁珠分离等技术从细胞、分子多层面水平研究PESV对非小细胞肺癌干细胞的作用，分析其作用与靶向DLL4/Notch1通路的关系，并探讨其关键机制，寻求PESV抑制非小细胞肺癌干细胞的作用靶点，为中医药的“辨靶论治”提供实验依据，也将有助于中药的创新性开发。

肿瘤干细胞在肺小细胞复发、转移中起关键作用，针对肿瘤干细胞异常信号通路进行靶向治疗成为肿瘤治疗的研究热点。传统中药具有多靶点、多环节抗肿瘤的作用优势，在抗肿瘤干细胞药物治疗中独具优势。DLL4/Notch1通路不但在肿瘤血管生成中而且在肿瘤干细胞自我更新中发挥重要作用。若以此通路为干预靶点，不但可直接抑制肿瘤干细胞，还可通过抑制其血管微环境间接抑制肿瘤干细胞。研究表明，蝎毒多肽提取物（PESV）兼具多靶点、多环节抑制肿瘤生长转移的特点，但其对肿瘤干细胞作用目前尚无研究报道。东亚钳蝎具有攻坚蚀疮、破淤散结、消除肿块的功效，因此符合中医“益气养精、解毒散结”治疗肺癌的重要学术观点和重要治法。本项目通过体、内外实验，从细胞、分子多层面水平研究PESV对非小细胞肺癌干细胞的作用，分析其作用与靶向DLL4/Notch1通路的关系，并探讨其关键机制，寻求PESV抑制非小细胞肺癌干细胞的作用靶点。本项目率先开展蝎毒多肽提取物分离提纯出抗肿瘤活性肽（PESV） 对非小细胞肺癌干细胞的调控作用及其与Notch1信号通路的关系。研究结果表明传统中药东亚钳蝎抗肿瘤活性肽（PESV）明显抑制非小细胞肺癌干细胞的干性，其作用机制可能且与Notch1相关。本研究结果为中医药的“辩靶论治”提供了实验依据，也将有助于中药的创新性开发。