Abstract
BackgroundIn our previous study using oligonucleotide microarrays, we revealed that transglutaminase 3 (TGM3) was remarkably down-regulated in head and neck cancer (HNC). However, the potential of TGM3 as a useful biomarker or molecular target for HNC is unclear.MethodsThe transcriptional and post-translational status of TGM3 in HNC cell lines and specimens was detected using real-time PCR and western blot analysis. Bisulfate-treated DNA sequencing was used to analyze the molecular mechanism of TGM3 gene silencing. In addition, the effects of TGM3 on the proliferation, colony formation and induction of apoptosis in vitro and tumorigenicity in vivo were investigated through exogenous expression of TGM3 in HNC cells. Immunohistochemistry was used to evaluate TGM3 expression in large HNC samples.ResultsTGM3 was down-regulated in HNC samples and cell lines (P < 0.0001). The hypermethylation of a promoter CpG island was one of the mechanisms of silencing the TGM3 gene in HNC. Exogenous expression of TGM3 in HNC cells could inhibit the proliferation and enhance the apoptosis of HNC cells in vitro and suppress tumor growth in vivo. In addition, TGM3 protein levels were strongly associated with the pathological differentiation of HNC tissues (P = 0.0037). Survival analysis revealed that low TGM3 expression was associated with worse overall survival (P = 0.0002), and TGM3 expression level was an independent predictor in patients with HNC.ConclusionsThe studies prove that TGM3, as a candidate tumor suppressor, contributes to the carcinogenesis and development of HNC and may serve as a useful biomarker for patients with HNC.
Highlights
Head and neck cancer (HNC), squamous cell carcinoma accounts for over 90%, is the sixth most common cancer in the world [1]
transglutaminase 3 (TGM3) is down-regulated in head and neck squamous cell carcinoma (HNSCC) samples and cell lines To confirm our high-throughput microarray data, semiquantitative RT-PCR and real-time RT-PCR analyses were performed to investigate the mRNA levels of TGM3 in 53 paired HNSCC specimens, 9 HNSCC cell lines, and normal primary head and neck epithelial cells
The transcription of TGM3 is regulated by DNA promoter methylation in HNSCC samples and cell lines To investigate the molecular mechanism of TGM3 gene silencing in HNSCC tumor samples and cell lines, all of the above-mentioned HNSCC cell lines lacking TGM3 expression were treated with the demethylation agent 5-Aza-dC and the histone deacetylase inhibitor trichostatin A (TSA)
Summary
Head and neck cancer (HNC), squamous cell carcinoma accounts for over 90%, is the sixth most common cancer in the world [1]. TGM3, encoded by the TGM3 gene, is widely expressed in the small intestine, brain, skin and mucosa [12]. Recent studies have revealed that the down-regulation of the TGM3 gene is closely linked with a variety of human cancer types, including laryngeal carcinoma, esophageal and oral squamous cell carcinoma (OSCC) [17,18,19]. Mendez et al reported that the TGM3 gene was differentially expressed in nodepositive and node-negative primary tumors in patients with OSCC, implying that the decreasing TGM3 expression might contribute to the metastatic potential of OSCC [20]. Whether the TGM3 gene might be a valuable diagnostic or therapeutic biomarker for cancer, especially for HNC, needs to be further investigated. The potential of TGM3 as a useful biomarker or molecular target for HNC is unclear
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