SPC25 is highly expressed in HCC and is associated with poor prognosis and metastasis. Silencing SPC25 significantly inhibits HCC cell invasion and migration. Gene expression profiling reveals that SPC25 primarily affects genes related to ECM-integrin interactions, including the ITGB4. Upregulation of ITGB4 partially reverses the decrease in invasion and migration caused by SPC25 silencing. Deletion of SPC25 and ITGB4 reduces phosphorylation of FAK, PI3K, and AKT, downstream elements of the integrin pathway. This evidence concerns the gene ITGB4 and hepatocellular carcinoma.