青蒿鳖甲汤通过mTOR自噬调控引起肺癌细胞“失巢凋亡”的机制研究

Lung cancer is one of the most common malignant tumor with high occurrence rate and death rate. Metastasis is the key factor for prognostic outcome, which comes from the autophagy-induced resistance against anoikis. mTOR signals modulates the autophagy through mTOR pathway. According to the TCM theory, qi-yin deficiency is the basis of lung cancer, and heat toxin is the appearance, suggesting that yin deficiency and heat toxin is the TCM pathogenesis of lung cancer metastasis. Accordingly, reinforcing yin and dispelling heat is the specific treatment for the TCM pathogenesis, and Qing Hao Bie Jia decoction is the classic formula of the treatment. Our preliminary study showed that this formula can effectively inhibit lung tumor growth and invasion in tumor-bearing rats with yin deficiency and heat toxin. Therefore, we propose a scientific hypothesis that Qing Hao Bie Jia decoction could prevent lung cancer metastasis through inhibition of mTOR signal mediated autophagy and activation of anoikis. This study plans to establish in situ transplantation tumor and metastasis xenograft model by using nude mice to verify the effect of Qing Hao Bie Jia decoction, determine its effect path and material basis, and clarify its molecular mechanism on mTOR-modulated autophagy in anoikis. This study will provide new method and scientific basis for clinical prevention of late-stage lung cancer metastasis.

肺癌是最常见的恶性肿瘤，转移是影响其预后的重要因素。转移是细胞自噬抵抗失巢凋亡的结果，受mTOR信号通路调控。中医认为，肺癌以气阴不足为本，热毒瘀血为标，阴虚热毒是肺癌转移的主要病机。滋阴透热是肺癌阴虚热毒的对证治法，以青蒿鳖甲汤为代表方剂。项目组前期基明确该方能有效抑制肺癌虚热证大鼠肿瘤生长和侵袭，由此提出科学假说：青蒿鳖甲汤能有效预防肺癌转移，其作用机制与mTOR信号通路介导肺癌细胞自噬调控引起的失巢凋亡有关。本项目拟建立裸鼠肺癌原位移植和转移模型，验证青蒿鳖甲汤药效作用的同时，从组织—细胞—分子层面揭示其防转移的路径和物质基础，并基于mTOR信号通路揭示该方调控自噬引起失巢凋亡的分子机制。本项目将为临床晚期肺癌转移的有效预防提供新的手段和科学依据。

肺癌是最常见的恶性肿瘤，转移是影响其预后的重要因素。转移是细胞自噬抵抗失巢凋亡的结果，受mTOR信号通路调控。中医认为，肺癌以气阴不足为本，热毒瘀血为标，阴虚热毒是肺癌转移的主要病机。滋阴透热是肺癌阴虚热毒的对证治法，以青蒿鳖甲汤为代表方剂。项目组前期基明确该方能有效抑制肺癌虚热证大鼠肿瘤生长和侵袭，由此提出科学假说：青蒿鳖甲汤能有效预防肺癌转移，其作用机制与mTOR信号通路介导肺癌细胞自噬调控引起的失巢凋亡有关。本项目通过建立斑马鱼异种移植模型、裸鼠肺癌原位移植和转移模型、裸鼠异位移植模型，验证青蒿鳖甲汤药效作用的同时，揭示其防转移的分子路径并探索相关物质基础，证实青蒿鳖甲汤通过mTOR信号通路调控自噬引起失巢凋亡的分子机制，并首次发现青蒿素B是其主要药效活性成分。本项目共发表SCI论文4篇，将为临床晚期肺癌转移的有效预防提供新的手段和科学依据。