論文 - 詳細
| RRC ID | 51585 |
|---|---|
| 著者 | Sakamoto T, Kobayashi S, Yamada D, Nagano H, Tomokuni A, Tomimaru Y, Noda T, Gotoh K, Asaoka T, Wada H, Kawamoto K, Marubashi S, Eguchi H, Doki Y, Mori M. |
| タイトル | A Histone Deacetylase Inhibitor Suppresses Epithelial-Mesenchymal Transition and Attenuates Chemoresistance in Biliary Tract Cancer. |
| ジャーナル | PLoS One |
| Abstract |
Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine-resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation. |
| 巻・号 | 11(1) |
| ページ | e0145985 |
| 公開日 | 2016-1-1 |
| DOI | 10.1371/journal.pone.0145985 |
| PII | PONE-D-15-26531 |
| PMID | 26726879 |
| PMC | PMC4699768 |
| MeSH | Animals Antineoplastic Agents / therapeutic use* Biliary Tract Neoplasms / drug therapy* Biliary Tract Neoplasms / pathology Cell Line, Tumor Drug Resistance, Neoplasm* Epithelial-Mesenchymal Transition / drug effects* Histone Deacetylase Inhibitors / pharmacology* Humans Mice Transforming Growth Factor beta1 / physiology Xenograft Model Antitumor Assays |
| IF | 2.74 |
| 引用数 | 33 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | TFK-1(RCB2537) |