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.
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.
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DOI：
10.1158/0008-5472.can-09-1298
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Li Y;VandenBoom TG 2nd;Kong D;Wang Z;Ali S;Philip PA;Sarkar FH
胰腺癌（PC）是美国第四大最常见的癌症死亡原因，PC的侵袭性部分归因于其内在和外在的耐药特性，这也与上皮间质转化（EMT）的获得有关。新出现的证据还表明，EMT 过程受到许多 microRNA (miRNA) 表达状态的调节，这些微小 RNA 被认为是肿瘤发生和进展过程中各种生物和病理过程的关键调节因子。在本研究中，我们比较了吉西他滨敏感和吉西他滨耐药PC细胞之间的miRNA表达，并研究了用“天然药物”[3,3'-二吲哚基甲烷（DIM）或异黄酮]处理细胞是否会影响miRNA的表达。我们发现，在吉西他滨耐药细胞中，miR-200b、miR-200c、let-7b、let-7c、let-7d 和 let-7e 的表达显着下调，这些细胞表现出 EMT 特征，如成纤维细胞形态延长、上皮标志物 E-钙粘蛋白表达较低、间充质标志物（如波形蛋白和 ZEB1）表达较高。此外，我们发现通过转染研究或用 DIM 或异黄酮处理吉西他滨耐药细胞来重新表达 miR-200 会导致 ZEB1、slug 和波形蛋白下调，这与导致上皮形态的 EMT 表型的形态逆转一致。这些结果首次提供了实验证据，表明 DIM 和异黄酮可以作为 miRNA 调节剂，导致 EMT 表型逆转，这对于设计 PC 的新疗法可能很重要。
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.