Role of DNA methyltransferase 1 in pharyngeal cancer related to treatment resistance

Chen, Chih‐Cheng; Chen, Wen Cheng; Wang, Wen Hung; Lu, Chang; Lin, Paul; Lee, Kuan Der; Chen, Miao Fen

doi:10.1002/hed.21586

Cited by 11 publications

(12 citation statements)

References 34 publications

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“…However, directly inhibiting STAT3 by STAT3 siRNA had no obvious effect on DNMT1 expression. Phosphorylation of Akt kinase has been reported to be the mechanism responsible for enhanced expression of DNMT1 stimulated by IL-6 [33], [34]. When we blocked phosphoinositide 3 kinase/Akt signaling using the specific inhibitor LY294002, the attenuation of AKT activation was associated with decreased DNMT1.…”

Section: Discussionmentioning

confidence: 88%

IL-6 Expression Regulates Tumorigenicity and Correlates with Prognosis in Bladder Cancer

et al. 2013

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Identification of potential tumor markers will help stratify and identify a tumor's malignant potential and its response to specific therapies. IL-6 has been reported to be a predictor in various cancers. Therefore, the present study was performed to highlight the role of IL-6 in improving treatment and determining prognosis of bladder cancer. The human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments, in which biological changes after experimental manipulation of IL-6 were explored, including tumor behavior and related signaling in bladder cancer. In addition, clinical specimens from 85 patients with muscle-invasive, and 50 with non-muscle invasive bladder cancers were selected for immunohistochemical staining to evaluate the predictive capacity of IL-6 in relation to clinical outcome. The data revealed that IL-6 was overexpressed in the bladder cancer specimens compared with non-malignant tissues at both mRNA and protein levels. Positive staining of IL-6 was significantly correlated with higher clinical stage, higher recurrence rate after curative treatment, and reduced survival rate. Tumor growth and invasive capability were attenuated when IL-6 was blocked. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition (EMT), decreased DNA methyltransferase 1 expression and attenuated angiogenesis. In conclusion, our findings showed that IL-6 could be a significant predictor for clinical stage and prognosis of bladder cancer. Moreover, targeting IL-6 may be a promising strategy for treating bladder cancer.

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Section: Discussionmentioning

confidence: 88%

IL-6 Expression Regulates Tumorigenicity and Correlates with Prognosis in Bladder Cancer

et al. 2013

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“…IL-6 secretion in oral squamous cancer is facilitated by the microenvironment, in particular by stromal derived factor-1 [29]. Moreover, numerous projects have demonstrated that IL-6- induced hypermethylation and gene silencing may be mediated by DNMTs [18], [20], [31]–[33]. Taken together, we proposed that chronic inflammation stress in the oral cavity may promote tumorigenesis mediated by increased IL-6 to induce aberrant DNA methylation via increased DNMT3b activity.…”

Section: Discussionmentioning

confidence: 71%

Significance of DNMT3b in Oral Cancer

Chen

Lin

2014

PLoS ONE

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The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 –DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.

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“…It has been reported that a switch to accumulating DNA hypermethylation may be caused by the overexpression of DNA methyltransferases 25. Epigenetic gene silencing, promoted by DNMTs, has been observed in various malignancies, supporting the claim that DNMT genes are overexpressed in human cancers and during cellular transformation 7, 13, 26, 27. It has been reported that DNMT3b participates in the carcinogenesis of several cancer types,19, 28, 29 but the role of DNMT3b in esophageal SCC requires further investigation.…”

Section: Discussionmentioning

confidence: 90%

“…DNA methylation is typically mediated by DNA methyltransferases (DNMT); and, in mammalian genomes, there are 3 DNMT genes: DNMT3a and DNMT3b are responsible for de novo methylation and modify unmethylated DNA, and it is believed that DNMT1 is responsible for maintaining methylation patterns 10, 11. DNMT activity reportedly is increased in cancer cells and may be related to tumor aggressiveness and a poor prognosis 12‐14. Epigenetic silencing reported in gastric cancer and esophageal cancer is associated with overexpression of the DNMT family 5, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Lu²,

Lin³

et al. 2011

Cancer

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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-

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Role of DNA methyltransferase 1 in pharyngeal cancer related to treatment resistance

Abstract: DNMT1 may be a significant clinical predictor and a potential treatment strategy against head and neck cancer.

Cited by 11 publications

References 34 publications

IL-6 Expression Regulates Tumorigenicity and Correlates with Prognosis in Bladder Cancer

IL-6 Expression Regulates Tumorigenicity and Correlates with Prognosis in Bladder Cancer

Significance of DNMT3b in Oral Cancer

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

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