@Article{or.2025.067638,
AUTHOR = {Xingchao Song, Qiuyu Song, Xiao Ma, Anzhi Xu, Chunyan Tian},
TITLE = {MINDY1 Induces PD-L1 Deubiquitination to Promote Immune Escape in Hepatocellular Carcinoma by the Wnt/β-Catenin Pathway},
JOURNAL = {Oncology Research},
VOLUME = {33},
YEAR = {2025},
NUMBER = {11},
PAGES = {3583--3603},
URL = {http://www.techscience.com/or/v33n11/64073},
ISSN = {1555-3906},
ABSTRACT = { Background: Motif interacting with ubiquitin-containing novel DUB family-1 (MINDY1) could enhance the stability of programmed death-ligand 1 (PD-L1). The study aimed to investigate whether MINDY1 regulates the immune escape of hepatocellular carcinoma (HCC) mediated by PD-L1. Methods: MINDY1 and PD-L1 levels were detected through Western blot. The link between MINDY1 and PD-L1 was validated using the co-immunoprecipitation assay. The malignant biology of HCC cells was assessed through Cell Counting Kit-8, Carboxyfluorescein Succinimidyl Ester staining, transwell, and wound healing assay. CD8+ T cells were isolated and then co-cultured with HCC cells. Enzyme-linked immunosorbent Assay kits detected CD8+ T cytokine content. CD8+ T cell activation markers, PD-L1 ubiquitination levels, and Wnt/β-catenin pathway-associated protein levels were detected through Western blot. A HCC nude mouse model was developed, Ki-67 positivity and CD8+ T-cell infiltration were assessed through pathological staining and flow cytometry. Results: MINDY1 and PD-L1 levels were elevated in HCC. Overexpression of MINDY1 increased migrating and invading cells, elevated cell viability, and decreased apoptosis in HCC cells, leading to PD-L1 deubiquitination. Knockdown of MINDY1 reversed all of these indicators. Co-culturing with HCC cells overexpressing MINDY1 resulted in decreased proliferative capacity and cytotoxicity of CD8+ T cells, increased apoptosis, and decreased levels of cytokines and activation markers in CD8+ T cells. MINDY1 triggered Wnt/β-catenin pathway, Wnt activators further promoted PD-L1 deubiquitination and suppressed CD8+ T cell activation. MINDY1 overexpression increased PD-L1 and Ki67 positivity level in HCC tumors, suppressed CD8+ T-cell infiltration. Conclusion: MINDY1 promotes PD-L1 deubiquitination and inhibits CD8+ T cell activation by stimulating the Wnt/β-catenin pathway, consequently promoting HCC tumor immune escape.},
DOI = {10.32604/or.2025.067638}
}