CCT4 as a prognostic biomarker correlated with immune infiltration and hepatocyte dedifferentiation in hepatocellular carcinoma.

BACKGROUNDCCT4 is a key molecular chaperone and its dysfunction may impair actin or microtubule assembly, potentially driving hepatocellular carcinoma (HCC) progression. However, its roles in multiple cell types and tumor microenvironment infiltration in HCC remain unclear. This study aimed to investigate the biological functions of CCT4 in HCC by integrating single-cell and bulk transcriptomic data.

METHODSCCT4 expression in HCC was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Functional analyses were conducted via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Furthermore, Cox regression analysis and nomogram construction were employed to assess patient prognosis. Immune infiltration was evaluated with CIBERSORT, and drug sensitivity was tested using the CellMiner database. Hepatocyte features were analyzed using single-cell RNA-seq tools, including Cellular Trajectory Reconstruction Analysis using gene Counts and Expression (CytoTRACE) for stemness and CellChat for cell-cell communication.

RESULTSCCT4 showed significant overexpression in HCC tissues and was associated with clinical features such as age and tumor node metastasis (TNM) stage. Functional analyses linked co-expression genes of CCT4 to ribosomal biogenesis and protein folding. Cox regression and nomograms confirmed CCT4 as an independent prognostic factor for HCC. Correlations with nine immune cell types were observed through immune infiltration analysis. Drug sensitivity analysis revealed that HCC patients with high expression of CCT4 were resistant to sorafenib and other drugs. Single-cell analysis revealed that elevated CCT4 expression was enriched in pro-metastatic hepatocyte clusters, associated with increased hepatocyte proportions and poor differentiation, with weakened T/natural killer (NK) cell interactions in tumors.

CONCLUSIONSCCT4 is overexpressed in HCC, linked to poor prognosis, and may drive tumor progression via pro-metastatic hepatocyte dedifferentiation and immune shifts.