Abstract
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Objectives Brahma-related gene 1 (BRG1), the catalytic subunit of SWI/SNF chromatin-remodeling complex functions DNA double strand breaks (DSB) repair. The strategy of this study is increasing I-131 therapeutic effect by overexpressing BRG1 bromodomain (BRD) as a competitor resulting inefficient DSB repair.
Methods FRO anaplastic thyroid cancer cells which containing a luciferase reporter gene (effluc) were transfected with human sodium iodide symporter gene (pMSCV-oNIS) for radioiodine therapy. pMX-BRG1-BRD retro-viral vector was used to establish BRG1-BRD overexpressing FRO-oNIS cells. BRG1-BRD overexpression in FRO-oNIS cells was confirmed by western blot. Tumor cells were subcutaneously implanted into BALB/c nude mice. Animal SPECT/CT imaging was performed at 1 hr after I-131 treatment (0.5 mCi). To investigate the effect of BRD on I-131 therapy, tumor size was measured with caliper and optical images were acquired by IVIS imaging system.
Results Clonogenic assay indicated that radiation sensitizing effect of BRG1-BRD in FRO-oNIS-BRD cells. The luciferase signal of FRO-oNIS tumors which do not overexpressing BRD are continued to increase 32 fold until 18 days. However, the luciferase signal of FRO-oNIS-BRD decreased until 6 days. Thereafter, the signal of these tumors increased, indicating that the FRO-oNIS-BRD tumors regrowth from 6 days after I-131 treatment. The luciferase signal of the FRO-oNIS-BRD tumors showed 4.9 times lower than the FRO-oNIS tumors at 10 days. Also, the size of the tumors measured as same pattern to images. The size of FRO-oNIS tumors and FRO-oNIS-BRD increased 13.7 and 1.2 fold, respectively.
Conclusions We have shown that radio-sensitizing effect induced by BRG1-BRD overexpression on radioiodine therapy, and our results indicating that BRG1-BRD overexpression could be used as a therapeutic gene by combination with NIS for reducing therapeutic dose of radioiodine.