Paired box gene 4 (PAX4) is a transcriptional modulator located on chromosome 7q32, and its expression is dysregulated in a variety of human cancers, suggesting that PAX4 may be important in multiple tumors as a driver gene.Here, we show that PAX4 promoted migration and invasion in human epithelial cancers by decreasing miR-144/451 expression levels.Accordingly, miR-144/451 suppressed the migratory and invasive phenotypes, even in PAX4-expressing cells.Mechanistically, miR-144/451 inhibited cancer cell metastasis by targeting the A disintegrin and metalloproteinase (ADAMs) protein family members ADAMTS5 and ADAM10, the dysregulation of which is associated with increased invasiveness and reduced patient survival in certain epithelial cancers, thereby indirectly affecting epithelial plasticity.This discovery suggests that a PAX4-miR-144/451-ADAMs axis regulates human epithelial cancer metastasis, thus opening up therapeutic possibilities for these cancer types.