SMAD4 and hepatocellular carcinoma: Although either miR-224 up-regulation or SMAD4 down-regulation alone did not show any significant association with overall patient survival (Fig. S6 in File S1), HCC patients with tumors which exhibits more than 2 fold up-regulated miR-224 and more than 1.5 fold down-regulated SMAD4 expression compared to the paired adjacent non-tumorous tissues were found to be significantly associated with poorer overall survival (p<0.05, Fig. 4B).