Although the role of copper (Cu) in promoting KRas-or BRaf-mutation driven cancers via activating MEK1/2 kinases is known, the mechanism by which the copper transporter SLC31A1 (CTR1) is upregulated in pancreatic cancer (PDAC, KRas mutation) is not defined. In this study, we provide evidence that MEK signal maintains a high level of SLC31A1 through silencing the expression of miR-124-3P (miR-124) via a novel MEK-DNMT1-miR-124 feedback loop in PDAC cells. Further, we reveal that miR-124 directly targets suppression of SLC31A1, and miR-124 introduction together withtetrathiomolybdate (TM) treatmenthampered pancreatic cancer growth in vitro and in vivo. Our results demonstrate that a SLC31A1-MEK-DNMT1-miR-124 feedback loop is an important pathway to maintain copper absorption and promote pancreatic cancer progression, and we hope to provide a Cu-chelation as an adjuvant treatment strategy, to block the progression in Kras mutant PDAC patients.