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 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.
Department of Radiation Oncology, Chang Gung Memorial Hospital, Chiayi, Taiwan. miaofen@adm.cgmh.org.tw
Miao-Fen
MF
Chen
Ming-Shian
MS
Lu
Paul-Yang
PY
Lin
Ping-Tsung
PT
Chen
Wen-Cheng
WC
Chen
Kuan-Der
KD
Lee
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000401:mortality; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D000097584:DNA Methyltransferase 3B
D014408:Biomarkers, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B