Down-regulation of miR-223 reverses epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells.

Abstract

Recent studies have demonstrated that acquisition of epithelial-to-mesenchymal transition (EMT) is associated with drug resistance in pancreatic cancer cells; however, the underlying mechanisms are not fully elucidated. Emerging evidence suggests that microRNAs play a crucial role in controlling EMT. The aims of this study were to explore the potential role of miR-223 in governing EMT in gemcitabine-resistant (GR) pancreatic cancer cells. To achieve this goal, real-time reverse transcription-PCR and western blot analysis were used to validate whether GR cells acquired EMT in AsPC-1 and PANC-1 cells. Invasion, migration, and detachment assays were performed to further identify the EMT characteristics in GR cells. The miR-223 inhibitor was used to determine its role in GR-induced EMT. We found that GR cells acquired EMT features, which obtained elongated fibroblastoid morphology, decreased expression of epithelial marker E-cadherin, and up-regulation of mesenchymal markers. Furthermore, we observed that GR cells are associated with high expression of miR-223. Notably, inhibition of miR-223 led to the reversal of EMT phenotype. More importantly, miR-223 governs GR-induced EMT in part due to down-regulation of its target Fbw7 and subsequent upregulation of Notch-1 in pancreatic cancer. Our study implied that down-regulation of miR-223 could be a novel therapy for pancreatic cancer.

• Authors: Jia Ma, Binbin Fang, Fanpeng Zeng, Cong Ma, Haijie Pang, Long Cheng, Ying Shi, Hui Wang, Bin Yin, Jun Xia, Zhiwei Wang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 3 Pg. 1740-9 (Jan 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25638153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• MIRN223 microRNA, human
• MicroRNAs
• Deoxycytidine
• Gemcitabine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, pharmacology)
• Down-Regulation
• Drug Resistance, Neoplasm
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Humans
• MicroRNAs (genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Gemcitabine