The present study employed various approaches including affinity chromatography, LC-MASS peptide identification, immunofluorescence analysis, co-IP and GST pull down assays to demonstrate HDGF directly binds to surface NCL and regulates the NCL membrane translocalization, NCL gene expression, NCL/PI3K/Akt pathway and oncogenic behaviours in hepatoma cells. This evidence concerns the gene AKT1 and hepatocellular carcinoma.