WAC is associated with malignant phenotypes and Wnt/β-catenin pathway activity in liver cancer cells

Liver cancer remains a major cause of cancer-related morbidity and mortality worldwide. WW domain-containing adaptor with coiled-coil (WAC) participates in multiple biological processes, including transcriptional regulation, autophagy, and cell cycle progression, but its role in liver cancer remains insufficiently defined. This study aimed to investigate the expression pattern, clinical relevance, biological function, and potential pathway association of WAC in liver cancer.

Public datasets, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), were analyzed to assess WAC expression and its association with clinicopathological features, prognosis, predicted drug sensitivity, and immune-related characteristics. WAC expression was further examined in liver cancer cell lines. Loss-of-function experiments were performed to evaluate the effects of WAC silencing on cell proliferation, migration, invasion, cell cycle distribution, and apoptosis. Transcriptomic analysis and molecular assays were used to explore pathways associated with WAC, and SKL2001 was applied to assess the involvement of Wnt/β-catenin signaling.

WAC was upregulated in liver cancer tissues and cell lines, and higher WAC expression was associated with adverse clinicopathological features and poorer survival outcomes. WAC knockdown suppressed liver cancer cell proliferation, migration, and invasion, induced G2/M phase arrest, and promoted apoptosis. Transcriptomic and molecular analyses indicated that WAC silencing was associated with reduced Wnt/β-catenin pathway activity. Activation of Wnt/β-catenin signaling by SKL2001 partially reversed the inhibitory effects caused by WAC knockdown. WAC expression was also associated with predicted sensitivity to several chemotherapeutic agents and immune microenvironment-related features. The proposed WAC-FZD10 association was based on computational prediction and requires experimental validation.

WAC is upregulated in liver cancer and is associated with malignant cellular phenotypes and Wnt/β-catenin pathway activity. These findings suggest that WAC may serve as a potential biomarker and therapeutic target candidate in liver cancer.