黄芩汤及主要代谢物调控胃癌肿瘤干细胞增殖及分化的机制研究

Gastric cancer remains one of the most common cancers in China. However the chemotherapy efficiency is only 40%. The main reasons are the recurrence of cancer stem cells and the burden of severe chemotherapy side effects. Our previous study has identified gastric cancer stem cells, which characterized by the capacity for self-renewal and differentiation, and resistance to most of chemotherapy drugs. It is need to adopt multi-target therapy strategy to systematically solve the problem of multi-drug resistance and side effects. As we all know, chinese herbal compound have significant advantage in Traditional Chinese Medicine. In recent years, Huang Qin Tang (HQT) and its extracts exhibit the anti-tumor activity with reducing side effects and increasing chemotherapeutic antitumor effects. In this study, we will pre-condition HQT by hydrochloric acid-β-glucuronidase to simulate in vivo metabolism process. In addition, we would like study the effect of HQT and its metabolites on gastric stem cell proliferation and differentiation by high-throughput screening method. At the same time, we are plan to real-time monitor the gastric cancer stem cells growth by in vivo molecular imaging. Furthermore, to understand the key regulatory protein and signal pathway will be screened by gene chip technology, and by gain or loss function study. Finally, the effect of HQT extract will be explored in clinical trial.

胃癌是我国高发肿瘤，目前化疗有效率仅40%左右，化疗失败的重要原因是肿瘤干细胞的存在及严重化疗副反应。我们前期研究发现胃癌肿瘤干细胞具有自我更新、多向分化及多药耐药特性，能够抵抗目前大多数化疗药物的治疗。要系统解决胃癌的多药耐药及化疗副作用的问题，需要多靶点的药物综合治疗，而中药复方具有明显优势。黄芩汤及其提取物近年来发现有多种活性成分具有抗肿瘤、减轻化疗副作用、增强化疗药物效果等功能。本实验拟采用盐酸-β-葡萄糖醛酸糖苷酶处理的方法模拟体内代谢过程，通过高通量筛选的方法研究黄芩汤及其代谢物对胃癌肿瘤干细胞的增殖及分化影响。同时本实验利用小动物活体成像的方法实时研究黄芩汤对胃癌肿瘤干细胞的影响，并通过基因芯片技术对黄芩汤影响的主要信号通路及主要节点蛋白，进行干扰阻断等分子生物学研究；最后在临床中验证黄芩对胃癌中肿瘤干细胞多靶点的影响。

胃癌是我国高发肿瘤，目前化疗有效率仅 40%左右，化疗失败的重要原因是肿瘤干细胞的存在及严重化疗副反应。我们前期研究发现胃癌肿瘤干细胞具有自我更新、多向分化及多药耐药特性，能够抵抗目前大多数化疗药物的治疗。要系统解决胃癌的多药耐药及化疗副作用的问题，需要多靶点的药物综合治疗，而中药复方具有明显优势。黄芩汤及其提取物近年来发现有多种活性成分具有抗肿瘤、减轻化疗副作用、增强化疗药物效果等功能。.在国家自然科学基金（No. 81274002）的支持下，我们通过对胃癌肿瘤干细胞培养条件的优化，培养出体外成球能力、体内成瘤能力更强的胃癌肿瘤干细胞，通过对黄芩汤有效成分的提取，制成黄芩汤标准品。进一步的研究提示：黄芩汤对胃癌干细胞具有一定的凋亡诱导效应，并鉴定验证了黄芩汤促进胃癌干细胞分化作用。同时我们研究发现了黄芩汤对晚期胃癌患者血清MMP-2、MMP-9表达的影响。.综上所述本研究主要的发现是：通过对黄芩汤有效成分的提取，制成黄芩汤标准品；黄芩汤对胃癌干细胞具有一定的凋亡诱导效应，并鉴定验证了黄芩汤促进胃癌干细胞分化作用。同时发现了黄芩汤对晚期胃癌患者血清MP-2、MMP-9表达的影响。因此黄芩汤的多靶点、多生物学活性的功能将有利于肿瘤的治疗，结合国内外、黄芩汤实验研究基础上开发针对抗肿瘤干细胞的活性成分并且研究其机制具有重要意义，将有力的推动中药现代化的研究。