丹参二萜醌通过AGPAT1 /mTOR通路改善脂代谢紊乱抑制肺癌转移的机制研究

Dysregulation of lipid metabolism is the key reasons to disorder the tumor microenvironment, which is the basis leading to the lost control of proliferation malignant growth invasion and metastasis of tumors.Regulating lipid metabolism to remain stable of tumor microenvironment is a breakthrough for lung carcinoma therapy, and meanwhile, can embody the character of TCM. It has discovered in our protophase study that diterpenoid tanshinone(DT) can inhibit the invasion and metastasis of lung cancer cell A549, the high-throughput genome sequencing 、Gene Ontology and gene-set enrichment analysis find its mechanism was closely related with lipid metabolism which was regulated by AGPAT1 to further activate Akt/mTOR pathway. Aim to identify the anti-lung carcinoma effects of DT and its mechanism, metastatic melanoma models and lentivirus infection of AGPAT1, together with Gene Ontology and gene-set enrichment analysis would apply to studied the mechanism of lipid metabolism, reveal the effects of dyslipidemia on tumor growth, and mechanism of DT in inhibiting the invasion and metastasis in lung cancer.

脂代谢紊乱是肿瘤微环境“稳态”破坏的关键原因，也是肿瘤发生发展侵袭和转移的基础。调节脂代谢紊乱维持肿瘤微环境“稳态”是防治肺癌转移的突破口，并能体现中医药整体观特色。前期研究发现，丹参二萜醌能明显抑制人肺癌A549细胞侵袭转移，高通量基因测序技术和Gene Ontology、KEGG 富集分析发现其作用机制与AGPAT1/mTOR通路导致脂代谢紊乱密切相关。为进一步探讨其作用机制，本研究以肺癌移植瘤模型、慢病毒感染方式，结合Gene Ontology和KEGG 富集分析，深入探讨丹参二萜醌通过AGPAT1/mTOR通路改善脂代谢紊乱调节肿瘤微环境，抑制肺癌转移的分子机制，揭示脂代谢异常对肿瘤生长的影响以及丹参二萜醌抑制肿瘤细胞侵袭转移的作用机制。

脂代谢紊乱是引起肿瘤微环境“稳态”破坏的关键因素，也是肿瘤发生发展、侵袭和转移的重要基础，靶向脂代谢信号通路的药物可起到抗肿瘤作用。研究表明，丹参二萜醌类成分参与了肺癌细胞代谢特别是脂肪酸的代谢过程，具有调节脂质代谢紊乱，改善肿瘤微环境的作用。本研究以肺癌转移瘤模型、慢病毒感染的方式，从脂代谢紊乱角度进一步探讨丹参二萜醌抑制肿瘤细胞侵袭转移的作用，明确了丹参二萜醌类成分改善肿瘤微环境进而抑制肺癌转移的重要作用，其作用机制与脂代谢相关蛋白CAVIN1和MYBL2密切相关。本项目的完成进一步拓宽丹参及其成分的抗肿瘤应用范围，赋予中医药活血祛瘀法治疗恶性肿瘤的作用内涵，促进丹参二萜醌类成分的开发应用；同时为肺癌早期肿瘤标志物的筛选和预后监测提供数据支持。