Suppressing UVRAG Induces Radiosensitivity by Triggering Lysosomal Membrane Permeabilization in Hypopharyngeal Squamous Cell Carcinoma.

Abstract

IntroductionRadiotherapy is one of the most important methods in the treatment of patients with hypopharyngeal squamous cell carcinoma (HSCC). However, radioresistance will be developed after repeated irradiation. Among many key factors contributing to radioresistance, enhanced autophagy is recognized as one of the most important. The ultraviolent irradiation resistance-associated gene (UVRAG) is reported to be a crucial gene involved in the process of autophagy. Here, we test whether UVRAG has effect on the radioresistance of HSCC.MethodsHSCC cell line Fadu cells were treated with irradiation to test levels of autophagy. Tumor tissues from primary and recurrent HSCC patients were tested by immunohistochemistry. Then, we knocked down UVRAG to test its role in cell growth and the malignant behaviors. Response of cells to treatment was examined using LDH release assay, immunofluorescence, Western blot analysis and colony formation.ResultsWe found that irradiation induced autophagy in Fadu cells. Immunohistochemistry of primary and irradiated HSCC tumor tissues showed that UVRAG was upregulated after irradiation treatment. Inhibiting UVRAG with siRNA interfered cell growth, cell cycle, malignant behaviors and autophagic flux in Fadu cells. Knocking down UVRAG increased DNA damage and cell death induced by irradiation. Finally, we found that inhibiting UVRAG induced lysosomal membrane permeabilization, which contributed to radiosensitization of Fadu cells.ConclusionOur findings supported the oncogenic properties of UVRAG in HSCC and inhibiting UVRAG increased radiosensitivity in HSCC by triggering lysosomal membrane permeabilization. Therefore, UVRAG might be a promising target in the treatment of HSCC.