IN a double-transgene mouse model of HBx and IRS1 that mimic human hepatocellular carcinoma, persistent activation and cross-talk of IN/IGF1, WNT/β-catenin, and Notch enhance HCC cell metastasis and invasiveness, and up-regulation of aspartate β-hydroxylase (ASPH) is central to these signaling cascades (31). Here, IRS1 is linked to hepatocellular carcinoma.