Project Details
Abstract
Background: Nasopharyngeal carcinoma (NPC) is a human malignancy in which cancer
cells arise from the epithelial cells of the nasopharynx tissue. In advanced stages, NPC is a
highly metastatic cancer. The mechanisms underlying the highly metastatic nature of NPC remain
unclear. Compelling evidence indicate that EBV is a causal agent of NPC and suggest that products
of EBV genome are involved in the development of the malignancy. In addition to viral proteins, EBV
also encodes several microRNAs. Recently, utilizing the next generation sequencing technology, we
discovered that the EBV-encoded microRNA BART9 was expressed at high levels in NPC tissues. The
abundance of BART9 was higher than the best documented human oncogenic microRNA, miR-21.
Computational analysis revealed that several migration-related pathways are enriched with putative
targets of BART9, including E-cadherin, a critical regulator in epithelial-mesenchymal transition
(EMT) and cell migration and invasion. Over-expression of BART9 decreased the mRNA and protein
levels of E-cadherin and induced a translocation of beta-catenin in NPC cells. BART9-expressing
cells displayed a fibroblast-like morphology with enhanced the migration and invasion capability.
In contrast, depleting endogenous BART9 reduced the migratory capability of EBV-positive NPC cells.
Interestingly, the seed sequence of BART9 was highly similar to the seed sequence of human miR-200
family miRNAs, a miRNA family frequently down-regulated in tumors, including NPC. miR-200 family
miRNAs have been shown to play a critical role in regulation of EMT and cell migration.
Over-expression of BART9 down-regulates the levels of miR-200 family miRNAs in NPC. These data
suggest that BART9 may promote cell migration and invasion by simultaneously regulating human
protein-coding genes and miRNAs in NPC.
Aim and strategy: In this proposal, we aim to elucidate the role of BART9 in NPC tumorigenesis.
Three specific aims are proposed. Firstly, we will use in vivo animal models to investigate the
effect of BART9 in the metastasis of NPC. Secondly, we will characterize the cellular events and
the molecular targets and pathways associated with BART9-mediated migration, invasion and tumor
metastasis. Finally, we will investigate the potential interaction between BART9 and human miR-200
family miRNAs.
Significance and future application: The ultimate goal of this study is to explore the potential of
targeting EBV-encoded microRNAs for NPC diagnosis, prognosis and therapeutics. The proposed studies
could advance our understanding of the biological functions and pathways regulated by BART9 and
provide useful strategies to control the progression of NPC. In addition, the knowledge gained from
this study will help to understand the interaction between virus- and host-encoded microRNAs. This
information can potentially be extended to other virus-encoded microRNAs and can be used in both
basic and translational research.
Project IDs
Project ID:PC10108-0892
External Project ID:NSC101-2320-B182-013-MY3
External Project ID:NSC101-2320-B182-013-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/12 → 31/07/13 |
Keywords
- EBV virus
- microRNA
- Cell migration
- Tumor metastasis
- Nasopharyngeal carcinoma (NPC)
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