Isoliquiritigenin 通过增强宿主抗肿瘤免疫力抑制乳腺肿瘤发展

The American journal of Chinese medicine Pub Date : 2024-01-01 Epub Date: 2024-09-30 DOI:10.1142/S0192415X2450071X
Chun-Lu Yuan, Xiao-Lu Yang, Lei Sun, Yi-Xin Jiang, Dan-Dan Zhang, Shuang Huang
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摘要

甘草的一种成分 Isoliquiritigen(ISL)已被证明对多种癌症具有抗肿瘤作用。在这项研究中,我们观察到 ISL 对免疫功能正常小鼠乳腺肿瘤发生的抑制作用明显强于免疫功能低下的小鼠。在探索造成这种差异的原因时,我们在接受 ISL 治疗的小鼠体内检测到了强大的 CD8[公式:见正文] T 淋巴细胞的肿瘤浸润,而在接受药物治疗的小鼠肿瘤中却看不到这种现象。此外,我们还发现 ISL 治疗后,实验性乳腺肿瘤和培养的乳腺癌细胞中的 PD-L1 均显著减少。在进一步的实验中,我们发现 ISL 能选择性地升高乳腺癌中的 miR-200c,并证实 PD-L1 mRNA 在小鼠和人类乳腺癌细胞中都是 miR-200c 的靶标。ISL对PD-L1的抑制与miR-200c/ZEB1/2的功能有关,因为(1)ISL减少了ZEB1/2;(2)敲除ZEB1/2导致PD-L1消失;以及(3)miR-200c antagomiR削弱了ISL减少PD-L1的作用。我们发现有证据表明,ISL通过同时拦截ERK和Src信号通路来降低PD-L1的水平。与临床发现的 PD-L1 抗体可提高以紫杉类药物为基础的疗法的疗效相一致,我们发现 ISL 在骨科鼠乳腺肿瘤模型中提高了紫杉醇的杀瘤效果。这项研究表明,ISL通过增强宿主的抗肿瘤免疫力来抑制肿瘤。
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Isoliquiritigenin Suppresses Breast Tumor Development by Enhancing Host Antitumor Immunity.

Isoliquiritigen (ISL), a constituent of licorice, has been shown to possess antitumorigenic effects in diverse cancer types. In this study, we observed that ISL suppressed breast tumor development significantly more effectively in immunocompetent mice than in immunocompromised ones. In exploring the cause of such a discrepancy, we detected robust tumor infiltration of CD8[Formula: see text] T lymphocytes in mice treated with ISL, not seen in tumors derived from vehicle-treated mice. Moreover, we found a dramatic reduction in PD-L1 in both experimental breast tumors and cultured breast cancer cells upon ISL treatment. In further experiments, we showed that ISL selectively elevated miR-200c in breast cancer and confirmed that PD-L1 mRNA is the target of miR-200c in both murine and human breast cancer cells. ISL suppression of PD-L1 was functionally linked to miR-200c/ZEB1/2 because (1) ISL diminished ZEB1/2; (2) knockdown of ZEB1/2 led to the disappearance of PD-L1; and (3) miR-200c antagomiR disabled ISL to reduce PD-L1. We found evidence that ISL reduced the level of PD-L1 by simultaneously intercepting the ERK and Src signaling pathways. In agreement with clinical finding that PD-L1 antibodies enhance efficacy of taxane-based therapy, we showed that ISL improved the tumoricidal effects of paclitaxel in an orthopedic murine breast tumor model. This study demonstrates that ISL-led tumor suppression acts through the augmentation of host antitumor immunity.

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