美洛昔康通过微小RNA-200/程序性死亡受体配体1途径抑制肝细胞癌进展并增强免疫治疗敏感性。
Meloxicam Inhibits Hepatocellular Carcinoma Progression and Enhances the Sensitivity of Immunotherapy via the MicroRNA-200/PD-L1 Pathway.
作者信息
Guangshun Sun, Guoqiang Sun, Xin Chen, Xiangyi Kong, Wubin Zheng, Zhitao Li, Zhiying Zheng, Hongyong Cao, Chengyu Lv, Yongxiang Xia, Weiwei Tang
机构信息
Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
出版信息
J Oncol. 2022 Feb 21;2022:4598573. doi: 10.1155/2022/4598573. eCollection 2022.
BACKGROUND
Hepatocellular carcinoma (HCC) has become the sixth most common cancer and the third leading cause of cancer death in the world. Although the research achievements of tumor immunotherapy have made great progress, especially the combination of immune targeted therapy has achieved good curative effect in HCC, but only a few patients are suitable for it and benefit from it. Therefore, there is an urgent need to find new effective drugs to treat HCC or to enhance the sensitivity of immunotherapy.
METHODS
Meloxicam, a COX2 inhibitor with strong anti-HCC potential, was screened from 800 small molecules approved by FDA. The effect of meloxicam on the proliferation, invasion, and migration of HCC cell lines was evaluated by cell phenotype analysis. The Human Protein Atlas database and the TISCH database were used to analyze COX2 data in single cells, and the TISIDB database was used to analyze the correlation of COX2 with immune function. The real-time quantitative polymerase chain reaction (qRT-PCR) and western blot were used to evaluate the level of PD-L1 and CD155 in HCC cell lines treated with meloxicam and further explore its possible mechanism. In vivo experiments were applied to verify the effect of meloxicam combined with anti-PD1 therapy on HCC tumor growth in mice.
RESULTS
Meloxicam can significantly inhibit the proliferation, invasion, and migration of HCC cells. The TISIDB database indicated that the COX2 was strongly associated with immunoinhibitors and immunostimulators. Meloxicam upregulated the level of PD-L1 in HCC cell lines and animal models. In terms of mechanism, meloxicam inhibited microRNA-200, thereby upregulating PD-L1. In vitro experiments showed that both meloxicam and anti-PD1 had inhibitory effects on the growth of HCC tumors. Compared with meloxicam and anti-PD1 alone, the combination therapy showed stronger antitumor properties. Immunohistochemical analysis confirmed that meloxicam enhanced the antitumor immune activity in the tumor microenvironment.
CONCLUSION
Our study showed meloxicam inhibited HCC progression and enhanced the sensitivity of immunotherapy via the microRNA-200/PD-L1 pathway.
背景
肝细胞癌（HCC）已成为全球第六大常见癌症和第三大癌症死亡原因。尽管肿瘤免疫治疗的研究取得了很大进展，特别是免疫靶向治疗的联合应用在HCC中取得了良好疗效，但只有少数患者适合并从中受益。因此，迫切需要寻找新的有效药物来治疗HCC或提高免疫治疗的敏感性。
方法
从美国食品药品监督管理局（FDA）批准的800种小分子中筛选出具有强大抗HCC潜力的COX2抑制剂美洛昔康。通过细胞表型分析评估美洛昔康对HCC细胞系增殖、侵袭和迁移的影响。利用人类蛋白质图谱数据库和TISCH数据库分析单细胞中的COX2数据，并利用TISIDB数据库分析COX2与免疫功能的相关性。采用实时定量聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法评估美洛昔康处理的HCC细胞系中PD-L1和CD155的水平，并进一步探讨其可能机制。应用体内实验验证美洛昔康联合抗PD1治疗对小鼠HCC肿瘤生长的影响。
结果
美洛昔康可显著抑制HCC细胞的增殖、侵袭和迁移。TISIDB数据库表明COX2与免疫抑制剂和免疫刺激剂密切相关。美洛昔康上调了HCC细胞系和动物模型中PD-L1的水平。机制方面，美洛昔康抑制微小RNA-200，从而上调PD-L1。体外实验表明，美洛昔康和抗PD1对HCC肿瘤生长均有抑制作用。与单独使用美洛昔康和抗PD1相比，联合治疗显示出更强的抗肿瘤特性。免疫组织化学分析证实美洛昔康增强了肿瘤微环境中的抗肿瘤免疫活性。
结论
我们的研究表明，美洛昔康通过微小RNA-200/PD-L1途径抑制HCC进展并提高免疫治疗的敏感性。
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