Hum Mutat. 2026 May 12;2026:7210691. doi: 10.1155/humu/7210691. eCollection 2026.
ABSTRACT
BACKGROUND: Portal vein tumor thrombosis (PVTT) and portal hypertension are major contributors to gastrointestinal bleeding in hepatocellular carcinoma (HCC), yet the molecular programs linking vascular pathology, immune dysregulation, and bleeding risk remain incompletely defined.
METHODS: Bulk transcriptomic datasets related to PVTT (GSE77509 and GSE69164) and noncirrhotic portal hypertension (GSE77627) were analyzed using differential expression and weighted gene coexpression network analysis to identify robust disease-associated genes. A six-gene core signature was derived by intersecting differentially expressed genes with intramodular hub genes across datasets. Bleeding risk-associated biological programs, including coagulation, complement activation, angiogenesis, hypoxia, and inflammatory signaling, were quantified using ssGSEA. Immune infiltration was estimated using CIBERSORTx. Single-cell RNA-sequencing data from PVTT (GSE149614) were analyzed to resolve cell type-specific expression patterns and intercellular communication. Associations with survival, DNA methylation, immune infiltration, drug sensitivity, and molecular interactions were evaluated using public cancer genomics resources. Functional validation was performed using siRNA-mediated knockdown and drug treatment assays in HepG2 and Huh7 cells, followed by proliferation, colony formation, and wound healing assays.
RESULTS: Bleeding risk-related biological programs exhibited dataset-specific activation patterns and correlated with expression of the six-gene signature. Single-cell analysis revealed heterogeneous, cell type-specific expression across malignant, stromal, endothelial, and immune populations. OGFRL1 and WDR62 were significantly associated with overall survival and showed methylation-linked transcriptional regulation. Genetic silencing or pharmacological targeting of these genes significantly suppressed HCC cell proliferation, clonogenicity, and migration in vitro. Drug signature analysis and molecular docking supported potential interactions of nocodazole with OGFRL1 and testosterone with WDR62, which phenocopied knockdown effects.
CONCLUSION: These findings identify immune-coagulation dysregulation as a molecular link between PVTT, portal hypertension, and gastrointestinal bleeding risk in HCC and functionally validate OGFRL1 and WDR62 as biologically and therapeutically relevant targets.
PMID:42131723 | PMC:PMC13162123 | DOI:10.1155/humu/7210691