In the current study, the PI3K/Akt pathway was required for midkine-induced anoikis resistance that involved midkine-mediated ALK signaling in HCC cells, as evidenced by the results that suspension-cultured HCC cells treated with exogenous midkine showed an increase in pAkt expression; pretreatment with the Akt inhibitor MK2206 or Akt-specific siRNA effectively inhibited midkine-mediated anoikis resistance, and this response was accompanied by decreased expression of pAkt; consistently, in cells with ALK knockdown, midkine did not induce a significant increase in pAkt expression. Here, MDK is linked to hepatocellular carcinoma.