MUC1 Induced by Epstein-Barr Virus Latent Membrane Protein 1 Causes Dissociation of the Cell-Matrix Interaction and Cellular Invasiveness via STAT Signaling

Kondo, Satoru; Yoshizaki, Tomokazu; Wakisaka, Naohiro; Horikawa, Toshiyuki; Murono, Shigeyuki; Jang, Kyung Lib; Joab, Irène; Furukawa, Mitsuru; Pagano, Joseph S.

doi:10.1128/jvi.02222-06

Cited by 44 publications

(32 citation statements)

References 51 publications

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“…This was attributed to activation of the MUC1 promoter by binding of STAT1 and STAT3. LMP1 expression decreased cell adhesion in these cell lines -a phenomenon that was rescued by knocking down MUC1 expression using siRNA [89]. Therefore, LMP1-induced MUC1 expression may play an important role in the early stages of tumor cell detachment and dissemination, which may act in concert with other invasive and angiogenic factors to promote metastasis of EBV-infected tumor cells.…”

Section: Cell-cell and Cell-matrix Adhesionsmentioning

confidence: 92%

Role of The Epstein–Barr Virus-Encoded Latent Membrane Protein-1, LMP1, in The Pathogenesis of Nasopharyngeal Carcinoma

2009

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Although frequently expressed in Epstein-Barr virus (EBV)-positive malignancies, the contribution of the oncogenic latent membrane protein-1 (LMP1) to the pathogenesis of nasopharyngeal carcinoma remains to be fully defined. As a key effector in EBV-driven B-cell transformation in vitro, LMP1 also displays oncogenic properties in rodent fibroblasts, and exhibits similar effects in epithelial cells. LMP1 functions as a viral mimic of the TNFR family member, CD40, engaging a plethora of signaling pathways including: NF-kappaB, JNK/p38 (SAPK), PI3-kinase and ERK-MPK. The constitutive activation of these pathways appears central in the ability of LMP1 to induce multiple morphological and phenotypic alterations. Here we review the effects of LMP1 on epithelial cell growth transformation, and its putative role in the pathogenesis of nasopharyngeal carcinoma, focusing on key areas of proliferation, survival, cell motility and invasion.

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Section: Cell-cell and Cell-matrix Adhesionsmentioning

confidence: 92%

Role of The Epstein–Barr Virus-Encoded Latent Membrane Protein-1, LMP1, in The Pathogenesis of Nasopharyngeal Carcinoma

2009

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“…For example, Helicobacter pylori infection results in increased MUC1 expression and is a major contributor to gastric cancer74. MUC1 expression is also induced by the Epstein-Barr virus (EBV) latent membrane protein 1 and may contribute to tumorigenesis that is associated with chronic EBV infection75.…”

Section: Mucins Inflammation and Cancermentioning

confidence: 99%

Mucins in cancer: function, prognosis and therapy

2009

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Epithelia are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are largely unrecognized as effectors of carcinogenesis. However, both types of mucins are intimately involved in inflammation and cancer. Moreover, diverse human malignancies overexpress transmembrane mucins to exploit their role in signalling cell growth and survival. Mucins have thus been identified as markers of adverse prognosis and as attractive therapeutic targets. Notably, the findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.The epithelium is a laterally connected layer of cells with apical-basal polarity that separates multicellular animals from the external environment. Most epithelia are single cell layers and as such require robust defence mechanisms to maintain the integrity of the epithelial barrier. Secreted mucins appeared early in metazoan evolution as part of that defence and further emerged as more complex transmembrane structures that participate in the protection, repair and survival of epithelia in vertebrates. The mucins function in limiting the activation of inflammatory responses at the interface with the environment. Deregulation of mucin production has therefore provided an important link between inflammation and cancer. Moreover, carcinoma cells derived from epithelia, including those of the breast, prostate, lung and pancreas, commonly overexpress transmembrane mucins to exploit their role in promoting growth and survival. In this context, certain transmembrane mucins are sufficient to induce transformation and tumours in animal models, and thereby represent highly attractive targets for anticancer treatment. Somewhat paradoxically for what evolved as a protective mechanism for epithelial cells, transmembrane mucins are also aberrantly expressed in malignant haematopoietic cells. The exploitation of mucin function therefore seems to be a strikingly common theme for promoting the survival of diverse human carcinomas and haematological malignancies. Importantly for this Review, recent work has demonstrated that certain mucins are indeed direct drug targets and that inhibitors of mucin function block survival and tumorigenicity of human tumours in experimental models. Competing interests statementThe author declares competing financial interests: see web version for details. DATABASES Mucin family membersThe mucin family includes proteins that contain tandem repeat structures with a high proportion of prolines, threonines and serines (which constitute the PTS domain). Mucins are further defined by extensive glycosylation of the PTS domain through GalNAc O-linkages at the threonine and serine residues. The human mucin (MUC) family consists of membersdesignated MUC1 to MUC21 -that have been sub-classified into secreted and transmembrane forms. The se...

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“…In epithelial cell transformation, these include the activation of transcription factors (NF-κB, AP1, Id and Stats) (12–16), proteins that modulate adhesion and invasion (E-cadherin, MMP9 and MUC1) (17, 18), and signaling pathways (PI3K/Akt, ERK, p38 and JNK) (3, 11, 14). The growth of B lymphocytes from LMP1 transgenic mice requires the activation of Akt, NFκB and Stat3 signaling (19), of which Akt and NFκB pathways are also required for LMP1-induced transformation of the EBV-positive NPC cell line, C666-1 cells (20).…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein-1 Effects on Junctional Plakoglobin and Induction of a Cadherin Switch

2009

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Latent membrane protein-1 (LMP1) is considered the major oncoprotein of Epstein-Barr virus and is frequently expressed in nasopharyngeal carcinoma (NPC). LMP1 promotes growth and migration of epithelial cells, and the loss of plakoglobin has been identified as a contributing factor to LMP1-induced migration. Plakoglobin is a junctional protein that can also serve as a transcription factor in Tcf/Lef signaling. To determine the effects of LMP1 on the molecular and functional properties of plakoglobin, LMP1 was overexpressed in the NPC cell line C666-1. LMP1 did not affect plakoglobin stability but did decrease plakoglobin transcription. The resultant decreased levels of nuclear plakoglobin did not affect Tcf/Lef activity or the amount of plakoglobin bound to Tcf4. Although LMP1 induced and stabilized B-catenin, a protein with common binding partners to plakoglobin, the loss of plakoglobin did not affect its association with Tcf4. However, LMP1 did induce a cadherin switch from E-to N-cadherin, a process involved in cancer progression, and enhanced the association of junctional B-catenin with N-cadherin. LMP1 decreased overall levels of junctional plakoglobin but the remaining junctional plakoglobin was found associated with the induced N-cadherin. This increased association of junctional plakoglobin with N-cadherin was a distinguishing feature of LMP1-expressing cells that have reduced migration due to restoration of plakoglobin. Low levels of plakoglobin were also detected in human NPC tissues. These findings reveal that the effects of LMP1 on junctional plakoglobin and the initiation of a cadherin switch likely contribute to metastasis of NPC. [Cancer Res 2009;69(14):5734-42]

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MUC1 Induced by Epstein-Barr Virus Latent Membrane Protein 1 Causes Dissociation of the Cell-Matrix Interaction and Cellular Invasiveness via STAT Signaling

Cited by 44 publications

References 51 publications

Role of The Epstein–Barr Virus-Encoded Latent Membrane Protein-1, LMP1, in The Pathogenesis of Nasopharyngeal Carcinoma

Role of The Epstein–Barr Virus-Encoded Latent Membrane Protein-1, LMP1, in The Pathogenesis of Nasopharyngeal Carcinoma

Mucins in cancer: function, prognosis and therapy

Epstein-Barr Virus Latent Membrane Protein-1 Effects on Junctional Plakoglobin and Induction of a Cadherin Switch

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