RESUMEN
PURPOSE: Limited value is achieved in systemic chemotherapy for oral squamous cell carcinoma (OSCC), due to cancer cell resistance against cytotoxic agents. Tumor suppressor activities of selenium-binding protein 1 (SELENBP1) have been shown in multiple human cancers except for OSCC. The aim of this study is to clarify the biological functions and potential mechanism of SELENBP1 in OSCC. METHODS: SELENBP1 expression and its clinical significance in OSCC were analyzed from The Cancer Genome Atlas (TCGA) database. Quantitative polymerase chain reaction (qPCR) or western blot was applied to determine SELENBP1, NRF2 and KEAP1 mRNA or protein levels. Sulforhodamine B assay (SRB) was performed to examine the cytotoxic effects of 5-fluorouracil (5-FU) and cisplatin on OSCC cells. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the role of SELENBP1 in KEAP1 transcription. RESULTS: SELENBP1 downregulation is positively correlated with a poor prognosis for OSCC patients. SELENBP1 knockdown enhances resistance of OSCC cells to 5-FU and cisplatin, while SENENBP1 overexpression displays the opposite effects. Mechanistically, SELENBP1 reduces NRF2 protein levels by promoting its polyubiquitination and degradation. SELENBP1 induces KEAP1 transcription by binding to KEAP1 promoter. Downregulation of SELENBP1 is induced by miR-4786-3p binding to the 3' untranslated region (UTR) of SELENBP1. CONCLUSION: SENENBP1 is identified as a novel protective biomarker for OSCC patients. Targeting at the miR-4786-3p-SELENBP1-KEAP1-NRF2 signaling axis may enhance the efficacy of chemotherapy for OSCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Neoplasias de la Boca/genética , Factor 2 Relacionado con NF-E2/genética , Proteínas de Unión al Selenio/genética , Regiones no Traducidas 3'/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Cisplatino/farmacología , Fluorouracilo/farmacología , Genes Supresores de Tumor/fisiología , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Transducción de Señal/genéticaRESUMEN
BACKGROUND The aim of this study is to investigate the effects of Drynaria total flavonoids (DTF) on mandible microarchitecture, serum estrogen (E2), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) levels in an ovariectomy-induced osteoporosis rat model. MATERIAL AND METHODS Thirty female Sprague-Dawley rats were divided into 5 groups (n=6 per group): sham surgery, ovariectomy (OVX), and low-dose, middle-dose, and high-dose DTF. Mandibular osteoporosis was induced by ovariectomy; an equal amount of ovary-sized fat tissue was removed from the sham group. The DTF-treated groups were given DTF gavage at different doses for 12 weeks; the sham and OVX groups were given saline. After the treatment phase, the effects of DTF on the microarchitecture of the mandible were evaluated by measuring bone density, maximum load, morphometric parameters, and histopathological alterations. Serum E2, OPG, and RANKL levels were measured. RESULTS The OVX group showed obvious osteoporosis in the mandible and decreased serum E2 levels and OPG/RANKL ratio. The low-dose group did not show significant improvement in mandibular microstructure. The middle-dose group showed significantly ameliorated osteoporosis. The high-dose group had further improvement in bone microstructures and increase of OPG/RANKL over the middle-dose group. Furthermore, ovariectomy significantly decreased serum E2, but DTF treatment failed to restore serum E2 levels. CONCLUSIONS Ovariectomy can cause significant bone loss in the rat mandible and a decrease in serum E2 and OPG/RANKL. DTF significantly improved the mandibular microstructure and restored OPG/RANKL balance, but it did not restore the decreased serum E2 concentration following ovariectomy.