基于miR-21/mTOR/HIF1α信号轴研究丹灯纳米合剂通过活血化瘀双重作用防治口腔黏膜癌变的机制

活血化瘀是中医防治肿瘤的重要治法。我们前期发现活血化瘀中药丹参和灯盏花成分可有效抑制口腔黏膜癌变，并可抗肿瘤血管生成和诱导血管正常化；利用纳米载药技术将两种单药合成“丹灯纳米合剂”能显著提高抗肿瘤活性和生物利用度；并发现调控血管新生的mTOR信号及其上游miR-21和下游HIF1α、VEGF等分子参与口腔癌变。据此我们提出活血化瘀治法防治肿瘤的现代科学内涵——丹灯纳米合剂具有抗肿瘤血管生成和促血管正常化双重作用，通过改善缺氧微环境和干预miR-21阻断mTOR/HIF1α/VEGF通路的分子机制防治癌变。本项目将从分子、细胞、动物水平等多层次阐明丹灯纳米合剂对口腔癌变的干预机制：通过活血化瘀双重作用对4NQO致鼠舌黏膜癌变和DMBA致鼠颊囊癌变防治机制，对调控血管生成miR-21/mTOR信号轴的干预机制。本项目旨在研究活血化瘀中医治法的现代科学内涵，为口腔癌化学预防的中药研究提供新依据。

Promoting blood circulation and removing stasis is an important treatment method of traditional Chinese medicine in the prevention and treatment of tumor. We previously found that salvianolic acid B and breviscapine can inhibit oral carcinogenesis, and inhibit tumor angiogenesis and induce benign angiogenesis; the "Dandeng mixture" made by nano-drug loading technology can significantly improve the antitumor activity and bioavailability; and we also found that the mTOR signal and its upstream miR-21, downstream HIF1α, VEGF participate in oral carcinogenesis and angiogenesis. Hence, we put forward the modern scientific connotation of promoting blood circulation and removing stasis for anti-tumor, that is, Dandeng mixture has dual role of anti-tumor angiogenesis and promoting vascular normalization, and it can prevent cancer by improving hypoxia microenvironment and blocking miR-21 and mTOR/HIF1α/VEGF pathway. This project will clarify the anti-cancer effect of Dandeng mixture from the molecular, cellular and animal levels, clarify the prevention and treatment mechanism of the mixture on 4NQO-mouse tongue mucosa carcinogenesis and DMBA-golden hamster cheek pouch carcinogenesis through promoting blood circulation and removing blood stasis, and influence the new mechanism of miR-21 and its mTOR signal axis regulating angiogenesis. This project focuses on the modern scientific connotation of traditional Chinese medicine for promoting blood circulation and removing stasis, providing new ideas for the research and development of chemopreventive drugs for oral cancer.