Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma

Kanamoto,Ayako; Ninomiya,Itasu; Harada,Shinichi; Tsukada,Tomoya; Okamoto,Koichi; Nakanuma,Shinichi; Sakai,Seisho; Makino,Isamu; Kinoshita,Jun; Hayashi,Hironori; Oyama,Katsunobu; Miyashita,Tomoharu; Tajima,Hidehiro; Takamura,Hiroyuki; Fushida,Sachio; Ohta,Tetsuo

doi:10.3892/ijo.2016.3712

Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma

Authors:
- Ayako Kanamoto
- Itasu Ninomiya
- Shinichi Harada
- Tomoya Tsukada
- Koichi Okamoto
- Shinichi Nakanuma
- Seisho Sakai
- Isamu Makino
- Jun Kinoshita
- Hironori Hayashi
- Katsunobu Oyama
- Tomoharu Miyashita
- Hidehiro Tajima
- Hiroyuki Takamura
- Sachio Fushida
- Tetsuo Ohta
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Affiliations: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan, Center for Biomedical Research and Education, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
Published online on: September 27, 2016 https://doi.org/10.3892/ijo.2016.3712
Pages: 1859-1869
Copyright: © Kanamoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Esophageal carcinoma is one of the most aggressive malignancies, and is characterized by poor response to current therapy and a dismal survival rate. In this study we investigated whether irradiation induces epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) TE9 cells and whether the classic histone deacetylase (HDAC) inhibitor valproic acid (VPA) suppresses these changes. First, we showed that 2 Gy irradiation induced spindle cell-like morphologic changes, decreased expression of membranous E-cadherin, upregulated vimentin expression, and altered the localization of β-catenin from its usual membrane-bound location to cytoplasm in TE9 cells. Irradiation induced upregulation of transcription factors including Slug, Snail, and Twist, which regulate EMT. Stimulation by irradiation resulted in increased TGF-β1 and HIF-1α expression and induced Smad2 and Smad3 phosphorylation. Furthermore, irradiation enhanced CD44 expression, indicating acquisition of cancer stem-like cell properties. In addition, irradiation enhanced invasion and migration ability with upregulation of matrix metalloproteinases. These findings indicate that single-dose irradiation can induce EMT in ESCC cells. Second, we found that treatment with 1 mM VPA induced reversal of EMT caused by irradiation in TE9 cells, resulting in attenuated cell invasion and migration abilities. These results suggest that VPA might have clinical value to suppress irradiation-induced EMT. The reversal of EMT by HDAC inhibitors may be a new therapeutic strategy to improve the effectiveness of radiotherapy in ESCC by inhibiting the enhancement of invasion and metastasis.

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