Abstract
BackgroundThe 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.ResultsHere 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 IκBα (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.ConclusionsThus, 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.
Highlights
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
In B-cell lymphoma cell lines derived from Kaposi’s sarcoma herpes virus-associated malignancies like primary effusion lymphoma (PEL) including Epstein-Barr virus (EBV)-negative cell lines Bcbl-1 and BC-3, and EBV-positive JSC-1 cells, Fascin was only detectable at low amounts in the PELcell line JSC-1
In contrast to previous studies, which mainly focused on cells of epithelial origin and nasopharyngeal carcinoma (NPC) [42,43,45], we show in T lymphoid cells that latent membrane protein 1 (LMP1) is important for invasive migration, whereas it seems to be dispensable for attachment of invaded cells
Summary
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. According to the latency phase of EBV-associated malignancies, different latent genes are expressed [2]. In latency type I, which is represented by BL, only EBNA-1, EBER-and BART-RNAs are expressed, while in latency type II, which is typical for HL, NPC, gastric cancer and T-cell lymphomas, latent membrane protein 1 (LMP1) and 2A (LMP-2A) are expressed. Type III latency, which occurs in post-transplantation lymphoproliferative disease, is characterized by the expression of LMP1 and a variety of other latency-associated viral genes [2]. LCLs are usually derived from Epstein-Barr virus (EBV) infection of resting human B lymphocytes in vitro, resulting in continuous cell proliferation and transformation
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