Upon 5-FU and cisplatin treatment, ELF3-mediated transcription and secretion of SPINK1 increase, and potentiate HCC cells’ ability to promote tumor initiation, stemness, dedifferentiation and chemoresistance, by binding to EGFR and consequently driving the ERK-CDK4/6-E2F2 signaling cascade. Here, SPINK1 is linked to hepatocellular carcinoma.