SPINK1 and hepatocellular carcinoma: Of note, similar deregulation in ERK-CDK4/6-E2F2 signaling axis could also be validated in HCC cells treated with either recombinant SPINK1 or have SPINK1 stably overexpressed, with concomitant EGFR repressed, demonstrating EGFR as an important upstream regulator of the pathway (Supplementary Fig. S5a, f).