Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
Arch Biochem Biophys. 2022 Nov 30;731:109449. doi: 10.1016/j.abb.2022.109449. Epub 2022 Oct 23.
Persistent infection of human papillomavirus (HPV) and immune escape are the main causes of cervical cancer. E6/E7 encoded by HPV16 may be closely related to carcinogenesis. HPV infection may upregulate PD-L1 expression, resulting in immune escape and cervical cancerigenesis. Evidence indicates that miRNAs may mediate the regulation of E6/E7 on PD-L1. Therefore, we aimed to screen the miRNA, and further verify its expression and functions. Bioinformatics approaches were used to screen the miRNAs that mediate the regulation of E6/E7 on PD-L1. The expression of the miRNA and PD-L1 in HPV and HPV cervical cancer cells were compared, and the effect of E6E7 on them was evaluated. Then, the effect of the miRNA on PD-L1 was assessed by the Gain- and Loss-of-function test. Finally, in vivo experiments were conducted to verify the effects of the miRNA on tumor growth and survival of tumor-bearing mice. Six miRNAs were screened, of which miR-142-5p was identified. MiR-142-5p was downregulated and PD-L1 was upregulated in HPV cells after transfection of E6, E7, or E6/E7. The rescue test showed that the upregulation of miR-142-5p attenuated the effect of E6/E7 on PD-L1. The reverse relationship between PD-L1 and miR-142-5p was confirmed. In vivo experiments suggest that miR-142-5p upregulation inhibits the growth of the transplanted tumors by targeting PD-L1. MiR-142-5p acts as a tumor suppressor in cervical cancer. HPV16 E6E7 may promote the immune escape of cervical cancer cells by regulating the miR-142-5p/PD-L1 axis. Using miR-142-5p in tumor immunotherapy as a new strategy is proposed.
人乳头瘤病毒（HPV）的持续感染和免疫逃逸是宫颈癌的主要原因。HPV16 编码的 E6/E7 可能与致癌密切相关。HPV 感染可能上调 PD-L1 的表达，导致免疫逃逸和宫颈癌的发生。有证据表明，miRNA 可能介导 E6/E7 对 PD-L1 的调控。因此，我们旨在筛选 miRNA，并进一步验证其表达和功能。采用生物信息学方法筛选介导 E6/E7 对 PD-L1 调控的 miRNA。比较 HPV 和 HPV 宫颈癌细胞中 miRNA 和 PD-L1 的表达，并评价 E6E7 对它们的影响。然后，通过 Gain- 和 Loss-of-function 试验评估 miRNA 对 PD-L1 的影响。最后，进行体内实验验证 miRNA 对荷瘤小鼠肿瘤生长和生存的影响。筛选出 6 个 miRNA，其中 miR-142-5p 被鉴定。转染 E6、E7 或 E6/E7 后，HPV 细胞中的 miR-142-5p 下调，PD-L1 上调。挽救试验表明，miR-142-5p 的上调减弱了 E6/E7 对 PD-L1 的作用。证实了 PD-L1 和 miR-142-5p 之间的反向关系。体内实验表明，miR-142-5p 的上调通过靶向 PD-L1 抑制移植瘤的生长。miR-142-5p 在宫颈癌中起肿瘤抑制作用。HPV16 E6E7 可能通过调节 miR-142-5p/PD-L1 轴促进宫颈癌细胞的免疫逃逸。提出将 miR-142-5p 用于肿瘤免疫治疗作为一种新策略。
