Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma.
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.
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Ayako
A
Kanamoto
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Itasu
I
Ninomiya
Center for Biomedical Research and Education, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Shinichi
S
Harada
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Tomoya
T
Tsukada
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Koichi
K
Okamoto
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Shinichi
S
Nakanuma
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Seisho
S
Sakai
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Isamu
I
Makino
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Jun
J
Kinoshita
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Hironori
H
Hayashi
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Katsunobu
K
Oyama
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Tomoharu
T
Miyashita
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Hidehiro
H
Tajima
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Hiroyuki
H
Takamura
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Sachio
S
Fushida
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Tetsuo
T
Ohta
D000927:Anticonvulsants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000528:radiation effects; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D014965:X-Rays
D000927:Anticonvulsants; D014635:Valproic Acid