The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy‐three esophageal SCC...

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Published in:Cancer 2012-08, Vol.118 (16), p.4074-4089
Main Authors: Chen, Miao‐Fen, Lu, Ming‐Shian, Lin, Paul‐Yang, Chen, Ping‐Tsung, Chen, Wen‐Cheng, Lee, Kuan‐Der
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biomarkers, Tumor - metabolism
Carcinoma, Squamous Cell - enzymology
Carcinoma, Squamous Cell - mortality
Cell Line, Tumor
Cell Proliferation
DNA (Cytosine-5-)-Methyltransferases - physiology
DNA Methyltransferase 3B
Esophageal Neoplasms - enzymology
Esophageal Neoplasms - mortality
esophageal squamous cell carcinoma
Esophagus
Gastroenterology. Liver. Pancreas. Abdomen
Humans
Male
Medical sciences
Mice
Mice, Nude
Middle Aged
Neoplasm Invasiveness
Prognosis
Transplantation, Heterologous
Treatment Outcome
Tumors
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Summary:BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy‐three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P = .002) and reduced survival rates (P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial‐mesenchymal‐transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b‐positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance. Cancer 2012. © 2012 American Cancer Society. The incidence of nuclear DNA methyltransferase 3b (DNMT3b) immunoreactivity in specimens from patients with esophageal cancer is significantly higher than that in nonmalignant epithelium, and this incidence is linked positively to developing distant metastasis and to a poor prognosis. Targeting DNMT3b may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.26736