Herein, we show SPINK1 overexpression in the CD133+ liver tumor-initiating/propagating subset of HCC tumors to resist 5-FU and cisplatin treatment through activating ERK-CDK4/6-cyclinD1-E2F2 regulatory mechanism that eventually leads to maintenance of a more stemness and dedifferentiated state. This evidence concerns the gene CDK4 and hepatocellular carcinoma.