Abstract
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.
Highlights
The most frequently oral cancers are oral squamous cell carcinomas (OSCC) which are the most malignant tumors of the Head and Neck
The Immunohistochemical staining (IHC) data of tissue microarrays (TMA) slides confirmed this finding that DNMT3b was overexpressed in tumor tissues than the adjacent non-malignant epithelial tissues (Fig. 1C)
IHC of TMA slides revealed that the level of DNMT3b expression was higher in 76 (61%) cancer specimens than in adjacent nonmalignant oral epithelium
Summary
The most frequently oral cancers are oral squamous cell carcinomas (OSCC) which are the most malignant tumors of the Head and Neck. This aggressive epithelial neoplasm is associated with severe morbidity. Aberrant DNA methylation plays a key role in carcinogenesis, leading to epigenetic silencing of tumorsuppressor genes involved in cell cycle regulation, apoptosis and DNA repair [5,6]. We previously reported that activated IL-6 signaling was associated with the aggressive tumor behavior in oral cancer [19]. IL-6 was reported to promote tumorigenesis by alterinig DNA methylation [20]. The role of DNMT3b in OSCC in vitro and in vivo, and the correlation with the clinical outcomes of patients with OSCC using immunochemical staining analysis were investigated
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