USP18 Is Associated with PD-L1 Antitumor Immunity and Improved Prognosis in Colorectal Cancer.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, 2011-

Colorectal Neoplasms*/genetics ; Colorectal Neoplasms*/immunology ; Colorectal Neoplasms*/pathology ; Ubiquitin Thiolesterase*/genetics ; Ubiquitin Thiolesterase*/metabolism ; B7-H1 Antigen*/metabolism ; B7-H1 Antigen*/genetics; Humans ; Prognosis ; Cell Proliferation ; Cell Line, Tumor ; Female ; Male ; Gene Expression Regulation, Neoplastic ; Molecular Docking Simulation

Background: 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.
Methods: 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.
Results: 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.
Conclusions: In summary, USP18 shows great promise for research and clinical application as a potential target for CRC immunotherapy.

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81872706 National Natural Science Foundation of China; DJXSTD202405 Basic Medical Research and Translational Team

Keywords: PD-L1; USP18; anticancer immunity; colorectal cancer; immune checkpoint genes; tumor immune microenvironment

EC 3.4.19.12 (Ubiquitin Thiolesterase)
0 (B7-H1 Antigen)
0 (CD274 protein, human)
EC 3.4.19.12 (USP18 protein, human)

Date Created: 20240928 Date Completed: 20240928 Latest Revision: 20240930

20240930

PMC11430364

10.3390/biom14091191

39334957