Multimodal Single-Cell Network Analysis Identifies Basigin/Cluster of Differentiation 147 as a Tumor-Associated Signaling Hub in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) ranks among the leading causes of cancer mortality globally, driven by late diagnosis and inadequate sensitivity of biomarkers like α-fetoprotein for early or indeterminate lesions. Single-cell RNA sequencing (scRNA-seq) enables precise mapping of tumor heterogeneity and early malignant transitions. This study aims to apply scRNA-seq analysis to detect clinically important molecular patterns that define the early stages of malignant transformation in HCC and facilitate the diagnosis of small or ambiguous lesions.

METHODS

Here, we integrated 2 independent scRNA-seq datasets (GSE149614 and GSE189903) from non-tumor and HCC tissues. Following batch correction, hepatocyte subpopulations were delineated via clustering, differential expression, pseudotime, and Cellular Trajectory Reconstruction Analysis using gene Counts and Expression analyses to reconstruct normal-to-malignant trajectories. High-dimensional weighted gene coexpression network analysis identified stage-correlated modules, while CellChat and protein-protein interaction networks revealed intercellular signaling. Candidate expression was validated in paired human liver specimens via quantitative immunofluorescence.

RESULTS

We uncovered a hepatocyte continuum with escalating stemness and oncogenic activation (MYC, E2F, G2M pathways). The Hep-M20 module, most strongly stage-associated, pinpointed Basigin (BSG)/cluster of differentiation 147 (CD147) as a hub gene with monotonic pseudotime upregulation and stemness correlation (ρ = 0.48, P < 2.2 × 10-16). CellChat exposed a cyclophilin (peptidylprolyl isomerase A [cyclophilin A]/peptidylprolyl isomerase B [cyclophilin B])-BSG/CD147 axis mediating tumor-fibroblast-T cell crosstalk. Ex vivo, BSG/CD147 showed elevated HCC expression (P = 2.9 × 10-11) with superior diagnostics (AUC = 0.93-0.96; sensitivity 86%-87%; specificity 93%-97%), even in <2 cm lesions.

CONCLUSION

This multimodal analysis identifies BSG/CD147 as a tumor-associated signaling hub linked to hepatocyte state transitions and microenvironmental remodeling with potential utility for enhancing detection of small lesions in targeted imaging contexts.