Do EBV Encoded Small RNAs Interfere with Tumor Suppressor APC in EBV Associated Breast Cancers

摘要

Epstein Barr virus (EBV) infection in human is associated with variety of malignant diseases including Burkitt's Lymphoma (BL), nasopharyngeal carcinoma Hodgkin's disease and lymphoproliferative disorders and significant portions of breast cancers. EBV infection causes acute infectious mononucleosis but ultimately establishes persistent lifetime latent infection. In all latently infected cells EBV expresses two small non-polyadenylated RNAs (EBERs). Recent studies have shown that EBERs alone provide tumorigenic potential. We have identified that EBERs (which possess extensive secondary structure) has strong nucleotide sequence homology to the coding exon of kinesin superfamily of motor protein Kif3C. Kinesin is an essential member of the multiprotein beta-catenin degradation complex which includes tumor suppressor adenomatos poliposis coli (APO) and GSK3 beta. Beta-catenin, an activator of Wnt signaling pathway is activated inmany breast cancers. Here we demonstrate that EBER expression in mammary epithelial cell line BT549 induce elevated level of beta- cateninprotein and upregulation of its dependent genes. We also show that in epithelial cells EBER RNA is processed into 19 base small RNA which is homologous to a 3'-noncoding region of Kif3O mRNA. Further we demonstrate that Kif3O mRNA is also down-regulated inepithelial cells following EBER expression. Our pilot study thus provides intriguing data that suggests EBER mediated beta- cateninderegulation in epithelial malignancies which possibly takes place via tiny-RNA production from EBERs.