基于TMEM16A/CaCCs的当归抗肺腺癌作用及分子机制研究

当归广泛应用于中医肿瘤治疗，现代药理学实验也证实了它的抗肿瘤作用，但机制仍不甚清楚。研究发现TMEM16A编码的钙激活氯通道（TMEM16A/CaCCs）参与部分恶性肿瘤发病并影响预后，被认为是TMEM16A/CaCCs高表达型肿瘤治疗的药物作用新靶点。我们前期发现当归及其活性成分如欧前胡素、蛇床子素及蒿本内酯等可显著抑制TMEM16A/CaCCs电流。提示当归抗肿瘤作用可能与TMEM16A/CaCCs相关。据此，本申请将在前期发现的基础上，以TMEM16A/CaCCs高表达型肺腺癌为切入点，利用膜片钳、分子生物学、分子对接及定向点突变等技术，揭示当归活性成分对TMEM16A/CaCCs的调节作用，在细胞及整体水平明确其抗肿瘤作用，并阐明它们的分子机制。本研究成果将对TMEM16A/CaCCs阻断剂的开发、当归及其活性成分新的药理学作用及机制等问题的揭示具有重要意义。

Angelica sinensis is widely used to treat tumors in traditional Chinese medicine, and modern pharmacological studies have also confirmed its antitumor effect. However, the molecular mechanism underlying the anticancer effects of Angelica sp. remains unclear. An increasing amount of evidence suggests that TMEM16A encoded Ca2+-activated Cl- channels (TMEM16A/CaCCs) overexpression is associated with a poor prognosis in patients with malignant tumors, and this provides new possible targets for potential treatment of TMEM16A-overexpressing cancers. Our previous study indicated that Angelica sp. and its active components, such as imperatorin, osthole and ligustilide, significantly inhibited recombinant TMEM16A/CaCC currents, which suggested that the antitumor effect of Angelica sp. may be related to TMEM16A/CaCCs. This project is designed to clarify the inhibitory effects of active Angelica sp. components on TMEM16A/CaCCs and the molecular mechanism using patch clamp, molecular docking, and the site mutation techniques. The anticancer effects and the underlying mechanism of active Angelica sp. components on TMEM16A-overexpressing cancers were explored using molecular biology technology including in vitro and in vivo techniques. The research will have important significance in development of TMEM16A/CaCC blockers, and in understanding the anticancer effects and mechanisms of Angelica sp. and their active components.