Since ER-dependent cell fate is associated with the activation of JNK/ERK [37], and the pro-survival role of activated ERK can be mediated by AKT phosphorylation and the involvement of PERK/eIF2a signaling [38–40], thus, in the present study, the down-regulated activation of ERK, AKT and PERK/eIF2a provided further explanation for the decreased incidence of HCC in Tpl2 knockout mice. This evidence concerns the gene MAP3K8 and hepatocellular carcinoma.