https://orcid.org/0000-0003-2874-8152
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Abstract
Background
CD276 is an emerging immune checkpoint molecule that has been implicated in various cancers. However, its specific role in hepatocellular carcinoma (HCC) remains unclear. This study examined the impact of CD276 on patient prognosis and the tumor microenvironment (TME).
Methods
The Cancer Genome Atlas (TCGA) database was utilized to evaluate CD276 expression in HCC and the association between CD276 and immune indicators was also analyzed. The signaling pathways correlated with CD276 expression were identified by gene set enrichment analysis (GSEA). Different algorithms were used to assess immune cell infiltration. The effect of CD276 knockdown on HCC cell phenotypes and its relationship with macrophage polarization was examined using the cell counting kit 8 (CCK-8) assay and co-culture system.
Results
CD276 was upregulated in HCC and associated with unfavorable clinical outcomes. Hgh CD276 expression was associated with enrichment of the G2/M checkpoint, E2F targets, and mitotic spindles. CD276 expression was correlated with the infiltration of immune cells, including high level of tumor-associated macrophages and low levels of CD8+ T cells. Knockdown of CD276 decreased HCC cell proliferation and increased apoptosis. CD276 silencing in HCC cells and co-culture with THP-1–derived macrophages had a regulatory effect on macrophage polarization and macrophage-mediated cell proliferation and migration.
Conclusion
CD276 expression in HCC is associated with unfavorable clinical outcomes and may contribute to the development of an immunosuppressive microenvironment. Specifically, CD276 was associated with alterations in immune cell infiltration, immune marker expression, and macrophage polarization during HCC progression, suggesting its potential as a prognostic indicator and promising target for immunotherapeutic intervention in HCC.
Abbreviations
HCC, hepatocellular carcinoma; TME, tumor microenvironment; GSEA, gene set enrichment analysis; APCs, antigen-presenting cells; IHC, immunohistochemistry; DEG, differential gene expression; logFC, logFoldChange; GSEA, Gene set enrichment analysis; TMB, tumor mutation load; TIDE, Tumor ImmunoDysfunction and Elimination; PMA, phorbol-12-myristate-13-acetate; DMEM, Dulbecco’s Modified Eagle Medium; FBS, fetal bovine serum; CCK-8, Cell Counting Kit 8; siRNA, short interfering RNA; OS, overall survival; TAMs, tumor-associated macrophages; EMT, epithelial-mesenchymal transition; TILs, tumor-infiltrating lymphocytes.
Data Sharing Statement
The data will be available from the corresponding author.
Ethics Approval and Informed Consent
This study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and was approved by the institutional ethics committee of Zhongshan Hospital, Fudan University (Approval No. B2022-164). Informed consent for all patients was waived by the committee due to the retrospective nature of this study. All included patients’ personal information is strictly confidential.
Disclosure
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.