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

Abstract

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 ¼ .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates (P ¼ .002) and reduced survival rates (P ¼ .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;118:4074-

IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus

“…As shown in Figure 3b, the IL-6 silencing vector reversed EMT changes, with increased E-cadherin expressions, and decreased matrix metalloproteinase (MMP)-9, vimentin and Snail, a repressor of E-cadherin expression. The activation of STAT3 signaling was reported to play important roles in the induction of aggressive tumor behavior and EMT changes in cancer [18], including cancers in the upper aerodigestive tract [8,19]. As shown in Table 1 and Figure 3c–d, positive staining for p-STAT3 was evident in 47% of the 173 cancer specimens, and a significant positive correlation was found in cancer specimen that expressed IL-6 and p-STAT3.…”

“…Data obtained from cell and xenograft tumor growth experiments revealed that inhibiting IL-6 resulted in slower tumor growth and reduced invasiveness. The transformation of an epithelial cell into a mesenchymal cell appears to be functionally relevant to the invasive characteristics of epithelial tumors, including esophageal cancer [19,29,30]. At the molecular marker level, EMT is characterized by the loss of E-cadherin and increased expression of invasion-related factors [31].…”

An association between overexpression of DNA methyltransferase 3B4 and clear cell renal cell carcinoma

“…demonstrated that in four different types of tumors, DNMT3B was significantly overexpressed, while DNMT1 and DNMT3A were only modestly overexpressed and with lower frequency [7]. Thus, the overexpression of DNMT3B, but not DNMT1 or DNMT3A, has been observed in several types of cancers, and suggests an important role for DNMT3B in tumorigenesis [8]. …”

“…While DNMT3B has been shown to play an important role in tumorigenesis [8], the DNMT3B gene encodes nearly 40 known splice variants that are expressed in distinct tissues and are modulated in a disease-specific manner [12]. Thus, it remains unclear how each individual splice variants may contribute to DNMT3B function in normal and disease conditions.…”

Akciğer Kanserli Hastalarda Plazma DNA Metiltransferaz ve Metil-CpG’ye Bağlanan Protein Seviyelerinin Değerlendirilmesi

“…Çalışmamızda akciğer kanseri ve kontrol bireylerin plazma DNMT3a seviyeleri arasında farklılık bulunmamıştır. DNMT3b DNA metilasyonunda önemli rol oynayan bir de novo metiltransferaz olup, yapılan çalışmalarda DNMT3b'nin, akciğer kanseri [26], skuamöz hücreli baş ve boyun kanseri [27], göğüs kanseri [28], özefagal ve gastrik kanser [29] …”