Targeting of DICE1 tumor suppressor by Epstein-Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma

摘要

Latent infection with Epstein-Barr virus (EBV) is associated with several types of malignancies including nasopharyngeal carcinoma (NPC), which is particularly more prevalent in Southern China. EBV expresses at least 44 mature microRNAs (miRNAs) to modulate the activity of viral and cellular RNAs, but the targets of these EBV-encoded miRNAs in NPC are not well understood. In this report, we characterized DICE1 tumor suppressor to be a cellular target of EBV miR-BART3* miRNA. miR-BART3* was abundantly expressed in NPC cells. The target site of miR-BART3* located in the 3′-untranslated region of DICE1 transcript was identified and characterized. Enforced expression of miR-BART3* or its precursor pre-miR-BART3 led to down-regulation of endogenous DICE1 expression. Inhibition of endogenous miR-BART3* in NPC cells with anti-miR-BART3* oligonucleotide inhibitor resulted in increased expression of DICE1 protein. On the contrary, expression of miR-BART3* overcame the growth suppressive activity of DICE1 and stimulated cell proliferation. Consistent with its tumor suppressive function, DICE1 was underexpressed in EBV-expressing NPC tumor tissues. Taken together, our findings suggest that EBV encoded miR-BART3* miRNA targets DICE1 tumor suppressor to promote cellular growth and transformation in NPC. What's new? While there is a known link between Epstein-Barr virus (EBV) and nasopharyngeal carcinoma (NPC), the roles of EBV and its oncoproteins in NPC tumorigenesis remain poorly understood. Here the authors looked at EBV-encoded microRNAs and their potential targets in NPC. They found that DICE1 tumor suppressor was a cellular target of an EBV miRNA abundantly expressed in transfected and infected cells as well as in NPC tumor samples. This is the first report of an EBV microRNA targeting a tumor suppressor in NPC. The findings provide a new mechanism in NPC tumorigenesis and reveal potential new targets for therapy.