芒柄花素基于胰岛素样生长因子1信号通路对结直肠癌放疗增敏作用及其分子机制的研究

Formononetin as a natural anti-tumor compound, has been known for high efficacy and low toxicity. However, currently there is no study showing whether and to what extent it enhances radiotherapy sensitivity. Our previous study has shown that Formononetin exerts an anti-tumor effect via FGFR2 inhibition. Meamwhile we intensively investigated that correlation between Growth Factor/Insulin Like Growth Factor axis and radiothearp in vitro,in vivo and in clinica studies. Our data demonstrated that the close relationship between IGF-1/IGF-1R signaling and tolerance to radiotherapy. The current study is designed to explore the in vivo and in vitro effect of Formononetin on radiotherapy sensitivity of colorectal which is manifested by change of cellular apoptosis, cell cycle arrest, DNA damage/repair,ultrastructure cell morphology as well as radiosensitivity in tumor nude mice. Furthermore, we were also endeavored to characterize the relationship between radiotherapy sensitization and anti-angiogenic effect as well as the mechanism by which Formonontin regulates IGF-1/IGF-1R and downstream signaling which involves Erk1/2/MAPT,PI3K/Akt etc. Our study will pave the way for development of Formononetin as a novel radiothearpy sensitization agent.

芒柄花素作为抗肿瘤药物具有天然、高效、低毒的特点，目前尚无研究探讨其放疗增敏作用。我们前期研究发现Formononetin作为一种新的FGFR2抑制剂产生抗肿瘤作用；此外，我们对“生长激素/胰岛素样生长因子轴与放疗关系”的大量临床基础研究，证实IGF-1/IGF-1R与直肠癌放疗耐受密切相关。本研究在体外及体内实验水平，从细胞凋亡、细胞周期阻滞、DNA损伤修复及细胞超微结构变化等方面研究Formononetin对结直肠癌细胞及荷瘤裸鼠的放疗增敏作用，并探讨这一过程中芒柄花素如何调控IGF-1/IGF-1R及其下游Erk1/2/MAPK、PI-3K/Akt信号通路及相关基因的表达，及与抗血管生成作用的关系，阐述Formononetin基于IGF-1/IGF-1R对结直肠癌放疗增敏的分子机制，为临床“Formononetin作为一种新的放疗增敏剂应用“提供理论和实验依据。

我们前期研究发现中药单体芒柄花素可能具有放疗增敏作用，本课题从体内、体外实验层面研究芒柄花素干预对结直肠癌细胞株放疗敏感性的影响。结果发现：（1）芒柄花素对结直肠癌细胞及荷瘤裸鼠具有放疗増敏作用，其机制与增加细胞凋亡、调节细胞周期及减少结直肠癌细胞DNA损伤修复能力有关；（2）芒柄花素通过抑制IGF-1R磷酸化、引起MDM2介导的IGF-1R泛素化，从而抑制IGF-1/IGF-1R及其下游Erk1/2/MAPK、PI-3K/Akt信号通路，同时p-ATM、RAD51在断裂位点的聚焦持续存在，从而抑制DNA损伤修复；（3）芒柄花素还能抑制结直肠癌移植瘤血管生成，其机制与调节细胞生成相关因子IGF-1R、EGFR、VEGFR、FGFR2 表达及相关信号通路Notch等有关。总结本科研团队前期及现有成果，建立了以GH/IGF轴为方向从中药库中筛选放疗增敏药物的流程。共发表论文67篇，SCI 38篇，被Nature、Lancet、Gastroenterology等顶级期刊多次引用，纳入1项国际meta分析。立项国自然3项，省部级课题6项，纳入国家重点研发计划“中医药现代化研究”专项。培养博士38名硕士81名。本课题为研究团队的主要研究方向之一，所得结果为“芒柄花素作为一种新的放疗增敏剂”及中药单体放疗增敏剂的研究及临床应用提供理论和实验依据，共发表SCI论文6篇，培养硕士研究生3名，博士研究生1名；申请专利4项，获得江苏省科学技术奖1项，获得江苏省中医院科技进步奖1项。