Although obesity (characterized by high levels of serum leptin) and deregulated expression of miRNAs are both functionally implicated in the pathogenesis of chemoresistance of pancreatic ductal adenocarcinoma (PDAC), the mechanistic link synchronize these two factors remain poorly understood. Here, we show that expression levels of obesity-associated miR-342-3p were significantly upregulated in gemcitabine (GEM)-resistant PDAC tissues and cells, and this upregulation was associated with poor postchemotherapy prognosis. Using pharmacological approaches, we observed that crosstalk between leptin and Notch signaling pathways regulated fundamentally the miR-342-3p expression in GEM resistant PDAC cells. Functionally, forced expression of miR-342-3p exhibited a prosurvival effect and potentiated GEM resistance, whereas inhibition of miR-342-3p expression noticeably ameliorated chemosensitivity in GEM -resistant PDAC cells. By employing bioinformatics analysis, point mutation and luciferase reporter assays, we further identified the 3'-UTR of tumor suppressor Kruppel-like factor 6 (KLF6) as the direct target of miR-342-3p. Therapeutically, stable expression of the exogenous KLF6 was sufficient to abrogate the pro-survival effects of miR-342-3p in GEM-treated PDAC cells. Taken together, these results suggest that leptin-elicited miR-342-3p upregulation mediates, at least partially, the GEM resistance through inhibition of KLF6 signaling in PDAC. Considering the indispensable function of miR-342-3p during adipogenesis, this obesity-associated miRNA may operate as a novel posttranscriptional integrator linking lipid homeostasis and pancreatic chemoresistance. (C) 2019 Elsevier Inc. All rights reserved.