EBV LMP1-Mediated NF-kappaB-Regulated Biomarkers and Potential Roles in

Nasopharyngeal carcinoma (NPC) is a prominent disease in Chinese population lived in southeastern region of China. NPC represents ~40% of the head and neck cancers and is notorious for its highly metastatic nature. The survival rate of NPC is ~92% at one year and ~50% at five years, with ~27% of patients with distant metastases after current treatment remedies. These data suggest more sensitive and comprehensive approaches for early detection, and new or supplementary methods for therapy are merited. More recent evidences suggest that inflammation and NF-κB signaling are involved in cancers associated with microbial infections. NPC is closely associated with a human herpesvirus, Epstein-Barr virus (EBV), and EBV-encoded oncogene Latent membrane protein 1 (LMP1) is expressed in ~70% of tumor tissues. LMP1, mimicking TNF receptor superfamily proteins, can activate NF-κB signaling through interaction with TNF receptor-associated factors (TRAFs). Previous study has generated NPC gene expression profiles by Affymetrix microarrays using NPC and adjacent normal tissues, and showed that many genes with altered expression in NPC are predicted or previously reported to be regulated by NF-κB signaling. Thus, we propose to identify genes that are regulated by NF-κB in NPC by ChIP-on-chip assay. In addition to the target gene discovery, we, in the first year, will also study a known NF-κB regulated gene, thymidine phosphorylase (TP). We will ask if TP can be a NPC biomarker. We will also evaluate the mechanism of TP regulation in NPC by EBV LMP1, and test the functional role of TP over-expression in NPC, for instance anti-apoptotic activity. In the second year, we plan to test other NF-κB-regulated genes identified in the first year. We will focus on those that are novel proteins and those are not reported in NPC before. In the third year, we will continue to examine the functions of target genes in NPC, and we plan to establish a panel of NF-κB-regulated biomarkers that may be useful for diagnosis and prognosis of NPC. Specific goals 1) To identify genes that are regulated in NPC biopsies through two NF-κB pathways by ChIP-on-chip experiments. 2) To determine the consensus target sequence of p52 based on ChIP-on-chip results 3) To examine the molecular mechanism of target genes in NPC and to determine the role of EBV LMP1 4) To examine potentials of target genes as NPC biomarkers in NPC

Project ID:PC9902-0296
External Project ID:NSC97-2320-B182-001-MY3