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 gemcitabinesensitive 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. [Cancer Res 2009;69(16):6704-12]

Modulation of Gene Expression and Cell-Cycle Signaling Pathways by the EGFR Inhibitor Gefitinib (Iressa) in Rat Urinary Bladder Cancer

“…Multiple important cell-cycle control genes are repressed by let-7, including cyclin D1, cyclin D3, cyclin A, CDK4 and CCNA2, CDC25A, CDK6, and CDK8 (51, 52). Decreased let-7 expression is linked to increased tumorigenesis and poor patient prognosis (53)(54)(55)(56). This is in agreement with our observation that a decrease in let-7c expression in tumors versus normal bladder epithelium and an increase in expression in Iressa-treated tumors versus control tumors.…”

Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan

“…26,27 Future studies should also analyze the effect of Let-7 and its genetic modulation in patients with early disease and in patients treated with chemotherapy. 28,29 …”

miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4

“…High priority must be given to understanding the mechanisms of occurrence and development of pancreatic cancer and identifying novel diagnostics and effective therapeutics (10,11). MiR-141 is a member of the miR-200 family that mainly affects the epithelial-mesenchymal transition (EMT) process (12)(13)(14)(15)(16)(17)(18). In addition, MiR-141 may repress hepatitis B virus (HBV) replication by targeting peroxisome proliferator-activated receptor a (PPARA; ref.…”