丹参酮ⅡA通过靶向TRAIL-receptor和ULBPs增强NK细胞抗非小细胞肺癌效应的作用及分子机制研究

中医药及其有效成分对NK细胞肿瘤免疫治疗具有重要的调控作用。中药丹参的主要活性成分丹参酮ⅡA具抑制肿瘤细胞增殖与侵袭转移，诱导肿瘤细胞凋亡等抗肿瘤作用，但目前未见其对NK细胞抗肿瘤作用调控的研究。我们前期研究发现，丹参酮ⅡA能明显促进NK细胞抗非小细胞肺癌的作用，显著上调肿瘤细胞表面TRAIL-receptor和ULBPs的表达，其机制可能与CHOP蛋白有关。故结合文献报道，本项目假说为：丹参酮ⅡA通过CHOP相关信号通路上调肿瘤细胞表面TRAIL-receptor和ULBPs表达，增强NK细胞对非小细胞肺癌细胞的识别与杀伤。为验证此假说，我们将首先阐明丹参酮ⅡA上调TRAIL-receptor和ULBPs表达的作用及其分子机制，再进一步阐明其通过此机制在体内外促进NK细胞的抗肿瘤效应，丰富丹参酮ⅡA的抗肿瘤分子机理，也为其临床与NK细胞抗肿瘤免疫治疗的联合应用提供理论依据与实验支持。

Traditional Chinese medicine and its active compounds play an important role in regulating the anti-cancer immunotherapy of NK cells. Tanshinone ⅡA, the main active compound of Salvia miltiorrhiza Bge., has lots of anti-tumor effects such as inhibiting the proliferation, invasion and metastasis of tumors cells, enhancing apoptosis of tumors cells, but there is no any study on its regulatory effect on NK cells anti-tumor function up to now. In the preliminary study, we found that Tanshinone ⅡA can promote the anti-small cell lung cancer effect of NK cells by significantly up-regulate the expression of TRAIL-receptor and ULBPs on the surface of tumor cells, and the mechanism of these phenomenons may related to CHOP. Therefore, combined with the existing reports, we propose the scientific hypothesis: Tanshinone ⅡA enhances the recognition and lysis of NK cells to non-small cell lung cancer cells by increasing the expression of TRAIL-receptor and ULBPs of tumor cells through CHOP-related signal pathway. For this purpose, we will first clarify the role and its molecular mechanism of Tanshinone ⅡA in up-regulating the expression of TRAIL-receptor and ULBPs, and then clarify the promotion effects in NK cells mediated anti-tumor effect through this mechanism in vivo and in vitro. This work will enriches the molecular mechanism of Tanshinone ⅡA, and will provide theoretical basis and experimental support for its further application combining with NK cells anti-tumor immunotherapy.