Dysregulation　of　miR-203-3p　and　miR-21-5p　has　been　identified　in　esophageal　cancer　(EC).　The　restoration　of　miR-203-3p　and　reduction　of　miR-21-5p　were　able　to　cause　tumor　suppression.　Here,　co-transfection　of　miR-203-3p　mimics　and　miR-21-5p　inhibitors　led　to　an　extraordinary　increased　expression　of　miR-203-3p　and　synergistically　inhibited　proliferation,　migration,　and　invasion　in　EC　cells.　Moreover,　we　found　that　Ran　GTPase　(Ran)　was　dramatically　inhibited　in　EC　cells　treated　with　the　co-transfection　of　miR-203-3p　mimics　and　miR-21-5p　inhibitors.　Finally,　in-vivo　studies　showed　that　overexpression　of　miR-203-3p,　combined　with　the　suppression　of　miR-21-5p,　significantly　co-inhibited　growth　of　tumors.　The　obtained　data　suggested　that　the　development　of　miRNA-based　combination　therapeutics　represents　a　promising　cancer　treatment　strategy.　Copyright　(c)　2018　Wolters　Kluwer　Health,　Inc.　All　rights　reserved.