1. NUAK1 acts as a novel regulator of PD-L1 via activating GSK-3β/β-catenin pathway in hepatocellular carcinoma.
- Author
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Yao CY, Tao HT, He JJ, Zhu FY, Xie CQ, Cheng YN, Li JQ, Liu ZZ, Hou CY, Liu XL, Fan YL, Fang D, and Lv XR
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Rats, Male, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, Female, Middle Aged, Disease Models, Animal, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Liver Neoplasms metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, B7-H1 Antigen metabolism, B7-H1 Antigen genetics, Glycogen Synthase Kinase 3 beta metabolism, Glycogen Synthase Kinase 3 beta genetics, beta Catenin metabolism, Gene Expression Regulation, Neoplastic, Signal Transduction
- Abstract
Background: NUAK1 is associated with metastasis and drug resistance in hepatocellular carcinoma (HCC). However, little is known about the immune functions of NUAK1 in HCC. Therefore, the aim of this study was to elucidate the novel role of NUAK1 in facilitating immune evasion in HCC and to investigate the mechanisms underpinning this process., Method: The levels of NUAK1 expression and the infiltration of CD8
+ T cells were assessed in tumor tissues from HCC patients and mice xenograft model. HCC cell lines were used to validate the role of NUAK1 in regulating the transcription of PD-L1, the diethylnitrosamine-induced HCC model was established and the expression levels of NUAK1 and PD-L1 proteins in the rat livers were detected. Western blotting, immunofluorescence, real time PCR, and immunohistochemical staining were used to investigate the underlying mechanisms by which NUAK1 regulates PD-L1 expression in hepatocellular carcinoma., Results: NUAK1 expression was negatively correlated with CD8+ T cell infiltration in tumor tissues from HCC patients and mice xenograft model. Both gain and loss of functions have identified NUAK1 promoted PD-L1 expression at transcriptional level in HCC cells. The increased expression of NUAK1 and PD-L1 proteins were observed in the rat livers of diethylnitrosamine-induced HCC model. Moreover, overexpression of NUAK1 promotes GSK3β Ser9 phosphorylation, β-catenin expression and nuclear accumulation in HCC cells. By contrast, knockdown of NUAK1 has opposite effects. Inhibition of GSK3β activity significantly promoted β-catenin expression and PD-L1 expression in HCC cells. IHC analyses of tumor tissues from HCC patients suggested that the levels of p-GSK3β and β-catenin were positively correlated with NUAK1 expression. Knockdown of β-catenin also reversed NUAK1-mediated PD-L1 expression in HCC cells., Conclusions: This study revealed a novel role for NUAK1, which promotes the transcriptional expression of PD-L1 by activating GSK3β/β-catenin signaling pathway, leading to immune escape of hepatocellular carcinoma. Registry and the registration no. of the study/trial: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: Approval of the research protocol by an institutional review board: The study was approved by the Ethics Committee of the first affiliated hospital of Henan University. Informed consent: Informed consent was obtained from each patient. Consent for publication: All authors approved the final manuscript and the submission to this journal. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).) more...- Published
- 2025
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