Abstract: Objective To investigate the inhibitory effect of intervention of glypican- 3( GPC3) gene transcription combined with antitumor drugs on hepatoma cell proliferation. Methods Four types of GPC3- shRNA plasmids were established and transfected into HepG2 hepatoma cells. Quantitative real- time PCR and Western blot were used to measure the mRNA and protein expression of GPC3 to analyze its association with hepatoma cell proliferation and apoptosis. The independent samples t- test was used for comparison of continuous data between any two groups,and a one- way analysis of variance was used for comparison between multiple groups. Results Among these four plasmids,shRNA1 had a transfection efficiency of > 85% in the transfection of HepG2 cells and a silence efficiency of 89. 3% at the mRNA level,and the protein expression of GPC3 was significantly inhibited( P < 0. 01). At 72 hours,the GPC3- shRNA1 co- intervention group had an HepG2 cell inhibition rate of 71. 1%,significantly different from that in the negative group( t = 18. 092,P < 0. 001),an inhibition rate of migration of 89. 1%,significantly lower than that in the negative group( t = 8. 326,P < 0. 001),and inhibition rates of HepG2 cell movement and invasion of 53. 6% and 60. 1%,which were significantly different from those in the negative group( t = 52. 400 and 48. 245,both P < 0. 001). The GPC3- shRNA1 co- intervention group had a β- catenin mRNA inhibition rate of 46. 9% and a Gli1 mRNA upregulation rate of 7. 4%,significantly different from those in the negative group( t = 30. 108 and- 3. 551,P < 0. 001 and P = 0. 009). At 24 hours,10 μmol/L sorafenib combined with shRNA1 had an inhibition rate of tumor cells of 52. 6% and 100 μmol/L sorafenib combined with shRNA1 had an inhibition rate of tumor cells of 79. 5%,which were significantly different from that in the control group( t = 23. 314 and50. 352,both P < 0. 001). The half- maximal inhibitory concentrations of sorafenib,rapamycin,and erlotinib for HepG2 were 4. 67 ± 1. 20μmol/L,7. 85 ± 2. 00 nmol/L,and 18. 36 ± 0. 56 μmol/L,respectively,and their combination with shRNA1 had an HepG2 cell inhibition rate of 95. 11%. Conclusion Intervention of GPC3 gene transcription with specific shRNA can inhibit hepatoma cell proliferation,migration and movement,and invasion ability,induce hepatoma cell apoptosis,and inhibit hepatoma cell proliferation when combined with antitumor drugs in a synergistic manner. This suggests that GPC3 may be an effective therapeutic target for liver cancer and that combined targeted therapy can provide better strategies for the treatment of liver cancer.