In addition, activation of the Ras/Raf/MEK/ERK pathway in HCC may be due to the down-regulation of Ras inhibitors Sprouty and Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred-1) and Spred-2 [50, 51]. This evidence concerns the gene MAPK1 and hepatocellular carcinoma.