Circulating miRNA-122 and miRNA-223 expression signatures across TNM stages of hepatocellular carcinoma in Egyptian patients: association with angiogenesis, apoptosis, and autophagy-related biomarkers

Abstract Background Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, largely due to delayed diagnosis and limited availability of reliable non-invasive biomarkers for early disease detection. Circulating microRNAs have emerged as promising minimally invasive molecular indicators because of their remarkable stability in serum and their involvement in liver tumor biology. This study aimed to evaluate the expression patterns and potential clinical relevance of circulating miRNA-122 and miRNA-223 across different TNM stages of HCC in Egyptian patients and to explore their association with molecular mediators of angiogenesis, apoptosis, and autophagy. Methods and results A total of 200 participants were enrolled, including 50 healthy controls and 150 patients with stage I–III HCC. Serum expression of miRNA-122 and miRNA-223 was quantified using quantitative real-time PCR, while AFP-L3, MAPK14, AKT1, vascular endothelial growth factor (VEGF), caspase-8, and beclin-1 were determined by ELISA. Circulating miRNA-122 expression was significantly increased in all HCC groups compared with controls, with the highest levels observed in stage III disease, indicating a clear stage-dependent upregulation pattern. In contrast, miRNA-223 expression was significantly reduced across all HCC stages, with the lowest levels detected in advanced-stage tumors. These expression changes were accompanied by significant increases in MAPK14, AKT1, VEGF, AFP-L3, liver enzymes, and bilirubin levels, together with significant reductions in caspase-8 and beclin-1, reflecting progressive enhancement of proliferative, angiogenic, and anti-apoptotic signaling pathways during HCC progression. Histopathological findings further confirmed the progressive architectural and cytological deterioration across TNM stages. Conclusions Circulating miRNA-122 and miRNA-223 exhibit distinct and stage-dependent expression signatures in Egyptian patients with HCC, supporting their potential utility as minimally invasive biomarkers associated with HCC and TNM stage. Their integration with AFP-L3 and key molecular mediators of tumor progression may provide a clinically relevant biomarker panel for improving HCC diagnosis and monitoring in hepatology practice.