Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells.

Abstract

Pancreatic cancer is the fourth most common cause of cancer death in the United States, and the aggressiveness of pancreatic cancer is in part due to its intrinsic and extrinsic drug resistance characteristics, which are also associated with the acquisition of epithelial-to-mesenchymal transition (EMT). Emerging evidence also suggests that the processes of EMT are regulated by the expression status of many microRNAs (miRNA), which are believed to function as key regulators of various biological and pathologic processes during tumor development and progression. In the present study, we compared the expression of miRNAs between gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells and investigated whether the treatment of cells with "natural agents" [3,3'-diindolylmethane (DIM) or isoflavone] could affect the expression of miRNAs. We found that the expression of miR-200b, miR-200c, let-7b, let-7c, let-7d, and let-7e was significantly down-regulated in gemcitabine-resistant cells, which showed EMT characteristics such as elongated fibroblastoid morphology, lower expression of epithelial marker E-cadherin, and higher expression of mesenchymal markers such as vimentin and ZEB1. Moreover, we found that reexpression of miR-200 by transfection studies or treatment of gemcitabine-resistant cells with either DIM or isoflavone resulted in the down-regulation of ZEB1, slug, and vimentin, which was consistent with morphologic reversal of EMT phenotype leading to epithelial morphology. These results provide experimental evidence, for the first time, that DIM and isoflavone could function as miRNA regulators leading to the reversal of EMT phenotype, which is likely to be important for designing novel therapies for pancreatic cancer.

• Authors: Yiwei Li, Timothy G VandenBoom 2nd, Dejuan Kong, Zhiwei Wang, Shadan Ali, Philip A Philip, Fazlul H Sarkar
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 16 Pg. 6704-12 (Aug 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19654291 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anticarcinogenic Agents
• Indoles
• Isoflavones
• MIRN200 microRNA, human
• MicroRNAs
• mirnlet7 microRNA, human
• Deoxycytidine
• 3,3'-diindolylmethane
• Gemcitabine

Topics

• Anticarcinogenic Agents (pharmacology)
• Cell Dedifferentiation (drug effects, genetics)
• Deoxycytidine (analogs & derivatives, therapeutic use)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epithelial Cells (drug effects, physiology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (pharmacology)
• Isoflavones (pharmacology)
• Mesoderm (drug effects, physiology)
• MicroRNAs (genetics)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Tumor Cells, Cultured
• Up-Regulation
• Gemcitabine