SNARK, a novel downstream molecule of EBV latent membrane protein 1, is associated with resistance to cancer cell death

Abstract

To investigate the effect of Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) on human cancer cells, we sought to identify and analyse potential target genes that were differentially expressed in the presence and absence of LMP1. LMP1 upregulated the expression of SNARK compared with the empty vector transfected control cells, which was confirmed by reverse-transcription polymerase chain reaction. Cytotoxicity assay showed that SNARK expression increased drug resistance in response to doxorubicin (P = 0.0009), whereas knockdown of SNARK by siRNA (siSNARK) effectively inhibited LMP-1-mediated increase of cell survival (P = 0.0131). The expression of anti-apoptotic genes such as BCL6 and BIRC2 was increased by SNARK, and knockdown of these genes decreased SNARK-mediated increase of cell survival. The associations of SNARK, BCL6, and BIRC2 and the presence of EBV were also observed in T-cell lymphoma cell lines, NKL and HANK-1. These results suggest that SNARK is a downstream cellular target of LMP1 in malignant cells and can be a novel candidate for therapeutic intervention of EBV-associated cancer.

Keywords:

• LMP1
• SNARK
• Epstein–Barr virus
• microarray
• cell lines and animal models
• neoplasia
• drug resistance
• lymphoma and Hodgkin disease