Epidermal growth factor (EGF) promotes high‐mobility group protein A2 (HMGA2) expression through the PI3K/AKT signaling pathway in hepatocellular carcinoma (HCC). EGF induced a significant increase in HMGA2 mRNA (A) and protein expression (B) in SNU‐368, SNU‐739, Huh‐7 and HepG 2 cells. *P < .05, **P < .01, ***P < .001 compared to control group, one‐way ANOVA, n = 6 per group. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 (20 µmol/L) could reverse EGF‐mediated upregulation of HMGA2 mRNA (C) and protein (D) expression in SNU‐368 cells. ***P < .001 compared to control group, one‐way ANOVA, n = 6 per group. EGF‐induced upregulation of HMGA2 mRNA (E) and protein (F) can be blocked by Akt inhibitor MK2206 (10 µmol/L) in SNU‐368 cells, whereas JAK inhibitor AG490 (20 µmol/L) and MEK inhibitor PD98059 (20 µmol/L) have no effects on EGF‐induced HMGA2 mRNA and protein expression. **P < .01, ***P < .001, one‐way ANOVA, n = 6 per group