TGM3, a candidate tumor suppressor gene, contributes to human head and neck cancer

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.

Significantly mutated genes and regulatory pathways in SCLC—a meta-analysis

“…TGM3 promoter CpG island hypermethylation has been observed in HNC and exogenous expression of TGM3 reduces tumor growth in vivo . Furthermore, low TGM3 expression is associated with poor overall survival [32]. There is also evidence for TGM3 to induce cell proliferation and migration in esophageal cancer by downregulating the NF-κB signaling pathway [33].…”

Galangin inhibits growth of human head and neck squamous carcinoma cells in vitro and in vivo

“…The HNSCC cell lines were cultured in Dulbecco's Modified Eagle's Medium (Gibco, Carlsbad, CA, USA) supplemented with penicillin (100 U/ml), streptomycin (100 lg/ml) and 10% (v/v) heat-inactivated fetal bovine serum (FBS) (Gibco), as described previously [18]. All cells were incubated at 37°C in a humidified 5% CO 2 atmosphere.…”

Transglutaminases in autoimmune and inherited skin diseases: The phenomena of epitope spreading and functional compensation

“…[ ] TGM3 expression is not restricted to skin; it also occurs in epithelia of tongue and oesophagus. While increase in tumor susceptibility has not been described in Tgm3‐/‐ mice, many human studies demonstrated the loss of TG3 expression associated with severity of tumors of epithelial origin (oesophageal or oral basal and squamous cell carcinomas) . Altered epithelial integrity due to the loss of TG3 may lead to increased inflammatory responses and drive a susceptibility to tumor progression.…”

“…Besides inherited skin disorders and GRDs, a diversity of human pathologies have been associated with an underlying TG dysfunction (Table ). This involves diabetes, male subfertility, schizophrenia, hereditary spherocytosis, coagulopathies, age‐related cataractogenesis and tumor formation …”