CELL INTELLIGENCE · 肿瘤细胞治疗研究

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide and shows significant heterogeneity. Cadherin 13 (CDH13) is abnormally expressed in various malignancies, but its role in HCC and the tumor microenvironment remains unclear.

This study aimed to systematically explore the expression, regulatory mechanisms, and potential functions of CDH13 in HCC using a multi-omics strategy.

We integrated transcriptomics, proteomics, spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), immunohistochemistry (IHC), clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing, chromatin immunoprecipitation sequencing (ChIP-seq), weighted gene co-expression network analysis (WGCNA), gene set variation analysis (GSVA), immune infiltration analysis, molecular docking, phenotypic analysis, and survival analysis.

In multiple cohorts, CDH13 mRNA was significantly upregulated in 5145 HCC samples (standardized mean difference (SMD) = 1.17) and associated with poor prognosis (hazard ratio (HR) = 2.06). Protein levels were elevated in 165 public and 476 clinical paired samples (361 from Guangxi Medical University, 115 from Yulin Red Cross Hospital; SMD = 2.48), mainly localized to the cytoplasm and membrane. Spatial transcriptomics showed CDH13 enrichment in tumor regions and spatial association with endothelial cells, which was confirmed in an independent HCC tissue section. Focusing on cell function, CRISPR/Cas9 knockout of CDH13 significantly inhibited proliferation in HCC cell lines such as SNU182, SNU739, HUH7, etc. Further analysis showed CDH13 was expressed in hepatocytes, endothelial cells, and hepatitis B virus (HBV)-infected regions; pseudotime analysis indicated late-stage upregulation in endothelial cells and activation of the macrophage migration inhibitory factor (MIF) pathway. IHC confirmed moderate CDH13 positivity in tumor cells and strong positivity in microvascular endothelial cells. CDH13-high endothelial cells were enriched in pyrimidine metabolism, oxidative phosphorylation, and propanoate metabolism. WGCNA and GSVA linked CDH13-related genes to angiogenesis, invasion, and metabolic reprogramming. ChIP-seq identified binding of Forkhead box A1 (FOXA1) to CDH13 regulatory regions. Clinically, CDH13 negatively correlated with regulatory T cells (Tregs, R = -0.311) and γδ T cells (R = -0.206), and positively with stromal scores (R = 0.400). High CDH13 predicted poor immunotherapy response (Area Under the Curve (AUC) = 0.745-0.795) and prognosis. Molecular docking shows a binding with docetaxel (-7.6 kcal/mol), while phenotypic analysis showed no obvious physiological toxicity.

CDH13 is highly expressed in HCC and may promote angiogenesis, immune evasion, and metabolic reprogramming via the FOXA1-CDH13 axis, suggesting its potential as a therapeutic target.