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

By Yiwei Li, T. Vandenboom, D. Kong, Zhiwei Wang, Shadan Ali, P. Philip, Fazlul H. Sarkar. Cancer Research, 2009

665 citations recorded by the source corpus.

Pancreatic cancer (PC) is the fourth most common cause of cancer death in the United States and the aggressiveness of PC is in part due to its intrinsic and extrinsic drug resistance characteristics, which is also associated with the acquisition of epithelial-to-mesenchymal transition (EMT). Emerging evidence also suggest that the processes of EMT is regulated by the expression status of many microRNAs (miRNAs), which are believed to function as key regulators of various biological and pathological processes during tumor development and progression. In the present study, we compared the expression of miRNAs between gemcitabine-sensitive and gemcitabine-resistant PC cells, and investigated whether the treatment of cells with “natural agents” [3,3′-diinodolylmethane (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 that 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 re-expression 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 morphological 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 PC.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3438a874f46ba4d44a525ff194e1e81a198353aa

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Citations in the corpus

The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective (2019, background): “Particularly, the EMT follows the loss of epithelial cell polarity and development of fibroblast‐like morphology (Figure 16; Li et al., 2009; Mego, Sendurai, Cristofanilli, & Cristofanilli, 2010; Tuhkanen et al., 2009).”
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “…manipulating epithelial plasticity is reinforced by studies showing that depletion of Zeb1, either chemically or by RNA interference, in mesenchymal-like cells results in a partial epithelial metaplasia and either gain of K-Ras dependency or drug sensitivity (Singh et al., 2009; Li et al., 2009b).”
The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer? (2010, background): “…agents, induce the expression of mir-200 family members and subsequently reverse the resistance of pancreatic cancer cells to gemcitabine (li et al, 2009b). recently, a direct pro-apoptotic function of mir-200c was discovered by showing that this mirna targets the apoptosis inhibitor…”
MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy (2011, positive): “These include antagonizing miR-21 and miR-221, or overexpressing miR-200 and let-7 , in cells that are resistant to gemcitabine”