Centromere protein I, a cell cycle checkpoint gene, accelerates tumor progression via the hippo pathway and mediates immune escape in hepatocellular carcinoma
image: This study presents a comprehensive investigation into the prognostic significance of CCCRGs in HCC. Notably, our research provides the first mechanistic evidence that CENPI promotes HCC malignant progression through dysregulation of the Hippo pathway, while also revealing its novel role in mediating immune evasion by inhibiting the recruitment of antitumor effector cells, including CD8+ T cells and NK cells, to the tumor microenvironment. Although our findings establish a correlation between CENPI overexpression and impaired immune cell infiltration in HCC, the precise molecular mechanisms underlying CENPI-driven immune suppression remain to be fully elucidated. Future studies should focus on dissecting the upstream regulators of CENPI expression, its interactions with immune checkpoint pathways, and its potential role in shaping the tumor immune landscape through metabolic reprogramming or cytokine modulation. Given its dual role in promoting tumor aggressiveness and facilitating immune escape, CENPI represents a promising therapeutic target for HCC treatment. Strategies targeting CENPI, either directly through gene silencing or indirectly via modulation of its regulatory networks, may offer a novel approach to simultaneously inhibit tumor growth and enhance antitumor immunity, potentially improving clinical outcomes for HCC patients.
Credit: Yunfu Cui, Jian Ma
Background and Aims
Cell cycle checkpoint-related genes (CCCRGs) are implicated in the development and progression of hepatocellular carcinoma (HCC). However, their precise roles and underlying mechanisms remain insufficiently characterized and require further investigation. This study aimed to explore the prognostic significance of CCCRGs in HCC, and to investigate the mechanism by which they promote the progression of HCC.
Methods
HCC datasets from The Cancer Genome Atlas and International Cancer Genome Consortium were analyzed to identify hub genes. A prognostic model was constructed and validated using Kaplan–Meier analysis, nomogram, calibration curves, decision curve analysis, and receiver operating characteristic analysis. Immune infiltration patterns were assessed using single sample gene set enrichment analysis, while pathway activities were evaluated via gene set variation analysis. Single-cell RNA sequencing data from GSE149614 were analyzed with Seurat and CellChat to investigate cell–cell communication. Patient-derived HCC specimens were examined through immunohistological evaluation, HCC cell lines were used for in vitro functional assays, and in vivo tumor growth was assessed through animal experiments.
Results
CCCRGs showed significant associations with prognosis, malignant biological behavior, and immune responses in HCC. Centromere protein (CENP) I was identified as a critical hub gene that markedly promoted HCC proliferation, metastasis, and epithelial–mesenchymal transition, while inhibiting apoptosis. Mechanistically, CENPI suppressed YAP phosphorylation, enhancing its nuclear translocation and thereby driving malignant progression. Additionally, CENPI impaired immune effector cell infiltration, likely by disrupting tumor antigen presentation and chemokine-mediated CD8+ T cell chemotaxis, thereby promoting immune escape.
Conclusions
This study presents a comprehensive investigation into the prognostic significance of CCCRGs in HCC. Notably, our research provides the first mechanistic evidence that CENPI promotes HCC malignant progression through dysregulation of the Hippo pathway, while also revealing its novel role in mediating immune evasion by inhibiting the recruitment of antitumor effector cells, including CD8+ T cells and NK cells, to the tumor microenvironment. Although our findings establish a correlation between CENPI overexpression and impaired immune cell infiltration in HCC, the precise molecular mechanisms underlying CENPI-driven immune suppression remain to be fully elucidated. Future studies should focus on dissecting the upstream regulators of CENPI expression, its interactions with immune checkpoint pathways, and its potential role in shaping the tumor immune landscape through metabolic reprogramming or cytokine modulation. Given its dual role in promoting tumor aggressiveness and facilitating immune escape, CENPI represents a promising therapeutic target for HCC treatment. Strategies targeting CENPI, either directly through gene silencing or indirectly via modulation of its regulatory networks, may offer a novel approach to simultaneously inhibit tumor growth and enhance antitumor immunity, potentially improving clinical outcomes for HCC patients.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2023-00127
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
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