CYP2A6 suppresses hepatocellular carcinoma via inhibiting SRC/Wnt/β-Catenin pathway

Patients with hepatocellular carcinoma (HCC) at advanced stages face limited treatment options, highlighting the urgent need for more effective early detection methods and advanced therapeutic modalities. Emerging evidence shows that multiple CYP450 proteins are involved in the pathogenesis of HCC. CYP1A2, CYP2E1 and CYP3A5 have been shown to modulate important signaling pathways, hereby inhibiting the proliferation and invasion of HCC cells. In this study we investigated the role of cytochrome P-450 2A6 (CYP2A6) in HCC progression, focusing on its potential as a diagnostic biomarker and therapeutic target. By analyzing TCGA and GEO databases, we found that the expression levels of CYP2A6 were significantly decreased in HCC compared to normal tissues. Overexpression of CYP2A6 resulted in reduced proliferation, migration, invasion, adhesion, tube-forming in PLC/PRF/5 and HepG2 cells in vitro, as well as tumorigenicity and metastasis in nude mice. Notably, the anti-HCC effects of CYP2A6 were independent of its metabolic functions. We demonstrated that CYP2A6 could bind to proto-oncogene tyrosine-protein kinase SRC (SRC) and inhibit the SRC/Wnt/β-Catenin pathway. Overexpression of SRC abrogated the inhibitory effects of upregulating CYP2A6 on the migration and invasion of PLC/PRF/5 cells. These results together suggest the potential of CYP2A6 as a biomarker and therapeutic target for HCC. Its modulation of the SRC/Wnt/β-Catenin pathway provides a new insight for HCC treatment.