青蒿琥酯通过cdc20下调PD-L1抗黑色素瘤增殖分子机制研究

免疫疗法是黑色素瘤治疗的有效策略，但PD-1/PD-L1结合产生的负向调控导致肿瘤免疫逃逸发生。研究发现降低肿瘤细胞PD-L1的表达可增强免疫治疗效果，改善黑色素瘤患者预后。课题组前期研究发现青蒿琥酯可有效激活免疫，抑制黑色素瘤细胞增殖，同时降低PD-L1的转录水平；进一步发现STAT3磷酸化在PD-L1转录过程中发挥重要作用，同时生物信息学结果显示cdc20是该过程的关键基因。我们推测：青蒿琥酯可能通过调控cdc20降低STAT3磷酸化，进而抑制PD-L1的转录，逆转肿瘤免疫逃逸，最终发挥抗黑色素瘤增殖作用。本项目拟于多种黑色素瘤细胞系、动物实验进一步确证青蒿琥酯抗黑色素瘤作用，采用基因敲降、回补等实验阐明青蒿琥酯通过下调cdc20/STAT3途径抑制PD-L1转录的分子机制。为青蒿琥酯应用于黑色素瘤临床治疗提供实验依据。

Immunotherapy is an effective strategy for the melanoma treatment. However, the negative regulation produced by the combination of PD-1/PD-L1 leads to tumor immune escape. Studies have found that reducing the expression of PD-L1 in tumor cells can enhance the effect of immunotherapy and improve the prognosis of patients with melanoma. Our previous researches found that artesunate effectively activated immunity, inhibited melanoma cell proliferation, reducing the transcription level of PD-L1. It was further shown that STAT3 phosphorylation plays an important role in the transcription process of PD-L1, and the results of bioinformatics revealed that cdc20 is a key gene in this process. Thus, we speculated that artesunate may reduce STAT3 phosphorylation by regulating cdc20, thereby inhibiting the transcription of PD-L1, reversing tumor immune escape, and ultimately exerting an anti-melanoma proliferation effect. This project intends to further confirm the anti-melanoma effect of artesunate on a variety of melanoma cell lines and animal experiments, and use gene knock-down and replenishment experiments to clarify that molecular mechanisms underlying artesunate inhibiting PD-L1 transcription by down-regulating the cdc20/STAT3 pathway, which provided experimental basis for the application of artesunate in the clinical treatment of melanoma.