We found that Tspan5 upregulation enhanced the expression of active ADAM10, NICD1 and Hes5 as well as the nuclear localization of NICD1, whereas Tspan5 downregulation decreased the expressions of active ADAM10, NICD1 and Hes5 in HCC cells and in xenograft sections of metastatic foci in mouse lungs. Here, ADAM10 is linked to hepatocellular carcinoma.