Mohr, C.F.* ; Kalmer, M.A.* ; Gross, C.* ; Mann, M.C.* ; Sterz, K. ; Kieser, A. ; Fleckenstein, B.W.* ; Kress, A.K.*
The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-κB in lymphocytes and contributes to their invasive migration.
Cell Commun. Signal. 12:46 (2014)
Background: The actin-bundling protein Fascin (FSCN1) is a tumor marker that is highly expressed in numerous types of cancer including lymphomas and is important for migration and metastasis of tumor cells. Fascin has also been detected in B lymphocytes that are freshly-infected with Epstein-Barr virus (EBV), however, both the inducers and the mechanisms of Fascin upregulation are still unclear. Results: Here we show that the EBV-encoded oncoprotein latent membrane protein 1 (LMP1), a potent regulator of cellular signaling and transformation, is sufficient to induce both Fascin mRNA and protein in lymphocytes. Fascin expression is mainly regulated by LMP1 via the C-terminal activation region 2 (CTAR2). Block of canonical NF-κB signaling using a chemical inhibitor of IκB kinase β (IKKβ) or cotransfection of a dominant-negative inhibitor of IκB (NFKBIA) reduced not only expression of p100, a classical target of the canonical NF-κB-pathway, but also LMP1-induced Fascin expression. Furthermore, chemical inhibition of IKKβ reduced both Fascin mRNA and protein levels in EBV-transformed lymphoblastoid cell lines, indicating that canonical NF-κB signaling is required for LMP1-mediated regulation of Fascin both in transfected and transformed lymphocytes. Beyond that, chemical inhibition of IKKβ significantly reduced invasive migration of EBV-transformed lymphoblastoid cells through extracellular matrix. Transient transfection experiments revealed that Fascin contributed to LMP1-mediated enhancement of invasive migration through extracellular matrix. While LMP1 enhanced the number of invaded cells, functional knockdown of Fascin by two different small hairpin RNAs resulted in significant reduction of invaded, non-attached cells. Conclusions: Thus, our data show that LMP1-mediated upregulation of Fascin depends on NF-κB and both NF-κB and Fascin contribute to invasive migration of LMP1-expressing lymphocytes.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
Publication type
Article: Journal article
Document type
Scientific Article
Thesis type
Editors
Keywords
Ctar ; Epstein-barr Virus ; Fascin ; Invasion ; Lmp1 ; Migration ; Nf-κb; Membrane-protein 1; Sarcoma-associated Herpesvirus; Latent Infection Membrane-protein-1; Actin-bundling Protein; Cell-lines; Hodgkins-disease; Nasopharyngeal Carcinoma; Signal-transduction; Burkitts-lymphoma; Oncogene Product
Keywords plus
Language
english
Publication Year
2014
Prepublished in Year
HGF-reported in Year
2014
ISSN (print) / ISBN
1478-811X
e-ISSN
1478-811X
ISBN
Book Volume Title
Conference Title
Conference Date
Conference Location
Proceedings Title
Quellenangaben
Volume: 12,
Issue: 1,
Pages: ,
Article Number: 46
Supplement: ,
Series
Publisher
BioMed Central
Publishing Place
London
Day of Oral Examination
0000-00-00
Advisor
Referee
Examiner
Topic
University
University place
Faculty
Publication date
0000-00-00
Application date
0000-00-00
Patent owner
Further owners
Application country
Patent priority
Reviewing status
Peer reviewed
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Immune Response and Infection
PSP Element(s)
G-501500-001
G-501500-005
Grants
Copyright
Erfassungsdatum
2014-08-13