Ebv-Encoded Mirnas Can Sensitize Nasopharyngeal Carcinoma To Chemotherapeutic Drugs By Targeting Brca1

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy. The high expression ofBART-miRNAs (miR-BARTs) during latent EBV infection in NPC strongly supports their pathological importance in cancer progression. Recently, we found that severalBART-miRNAs work co-operatively to modulate the DNA damage response (DDR) by reducing Ataxia-telangiectasia-mutated (ATM) activity. In this study, we further investigated the role ofmiR-BARTson DDR. The immunohistochemical study showed that the DNA repair gene,BRCA1, is consistently down-regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role ofBART2-3p,BART12,BART17-5pandBART19-3pin BRCA1 expression. The ectopic expression of these fourmiR-BARTssuppressed endogenous BRCA1 expression in EBV-negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenousmiR-BARTsactivities in C666-1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines usingmiR-BART17-5pandmiR-BART19-3pmimics reduced the DNA repair capability and increased the cell sensitivity to the DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest thatmiR-BARTsplay a novel role in DDR and may facilitate the development of effective NPC therapies.