College of Basic Medicine, Jiamusi University, Jiamusi 154007, China.
College of Public Health, Jiamusi University, Jiamusi 154007, China.
Biomolecules. 2024 Sep 21;14(9):1191. doi: 10.3390/biom14091191.
Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to targeted immunotherapy. The deubiquitinating enzyme USP18 is known to play an important role in various aspects of the immune response, but its role in tumor immunity in CRC remains unclear.
In this study, multiple online datasets were used to systematically analyze the expression, prognosis, and immunomodulatory role of USP18 in CRC. The effect of USP18 on CRC was assessed via shRNA-mediated knockdown of USP18 expression in combination with CCK-8 and colony formation assays. Finally, molecular docking analysis of USP18/ISG15 and programmed death-ligand 1 (PD-L1) was performed via HDOCK, and an ELISA was used to verify the potential of USP18 to regulate PD-L1.
Our study revealed that USP18 expression was significantly elevated in CRC patients and closely related to clinicopathological characteristics. The experimental data indicated that silencing USP18 significantly promoted the proliferation and population-dependent growth of CRC cells. In addition, high USP18 expression was positively correlated with the CRC survival rate and closely associated with tumor-infiltrating CD8+ T cells and natural killer (NK) cells. Interestingly, USP18 was correlated with the expression of various chemokines and immune checkpoint genes. The results of molecular docking simulations suggest that USP18 may act as a novel regulator of PD-L1 and that its deficiency may potentiate the antitumor immune response to PD-L1 blockade immunotherapy in CRC.
In summary, USP18 shows great promise for research and clinical application as a potential target for CRC immunotherapy.
与传统化疗和靶向治疗相比，免疫疗法改善了多种实体瘤的治疗前景，包括肺癌、结直肠癌（CRC）和黑色素瘤。然而，它仅对某些患者有效，因此需要寻找替代策略来进行靶向免疫治疗。去泛素化酶 USP18 已知在免疫反应的各个方面发挥重要作用，但它在 CRC 中的肿瘤免疫作用尚不清楚。
在这项研究中，使用多个在线数据集系统地分析了 USP18 在 CRC 中的表达、预后和免疫调节作用。通过 shRNA 介导的 USP18 表达敲低与 CCK-8 和集落形成测定相结合，评估 USP18 对 CRC 的影响。最后，通过 HDOCK 进行 USP18/ISG15 和程序性死亡配体 1（PD-L1）的分子对接分析，并通过 ELISA 验证 USP18 调节 PD-L1 的潜力。
我们的研究表明，CRC 患者的 USP18 表达显著升高，并且与临床病理特征密切相关。实验数据表明，沉默 USP18 可显著促进 CRC 细胞的增殖和群体依赖性生长。此外，高 USP18 表达与 CRC 生存率呈正相关，并且与肿瘤浸润的 CD8+T 细胞和自然杀伤（NK）细胞密切相关。有趣的是，USP18 与各种趋化因子和免疫检查点基因的表达相关。分子对接模拟结果表明，USP18 可能是 PD-L1 的新型调节因子，其缺乏可能增强 CRC 对 PD-L1 阻断免疫治疗的抗肿瘤免疫反应。
综上所述，USP18 作为 CRC 免疫治疗的潜在靶点具有很大的研究和临床应用潜力。
