Epstein-Barr virus Rta promotes invasion of bystander tumor cells through paracrine of matrix metalloproteinase 9

ABSTRACT Nasopharyngeal carcinoma (NPC), which is closely associated with the Epstein-Barr virus (EBV), is a highly metastatic malignant tumor. An important activity in tumor invasion and metastasis is that of the 92-kDa type IV collagenase or gelatinase, matrix metalloproteinase 9 (MMP-9), which mediates the degradation of the basement membrane and extracellular matrix. The expression of MMP-9 has been shown to be enhanced by the EBV oncoprotein, latent membrane protein 1 (LMP-1). LMP-1, which is expressed in NPC, has two essential signaling domains within the carboxy terminus, termed C-terminal activation regions 1 (CTAR-1) and CTAR-2. This study reveals that either signaling domain can activate the MMP-9 promoter and induce MMP-9 activity; however, LMP-1 deletion mutants lacking either CTAR-1 or CTAR-2 had a decreased ability to induce MMP-9 expression. The deletion of both activation regions completely abolished the induction of MMP-9 activity, while the cotransfection of both the CTAR-1 and CTAR-2 deletion mutants restored MMP-9 activity to levels produced by wild-type LMP-1. The NF-κB and activator protein 1 (AP-1) binding sites in the MMP-9 promoter were essential for the activation of MMP-9 gene expression by both CTAR-1 and CTAR-2. The induction of MMP-9 expression by LMP-1 and both CTAR-1 and CTAR-2 mutants was blocked by the overexpression of IκB. The tumor necrosis factor receptor-associated factor (TRAF) pathway also contributed to the activation of the MMP-9 promoter as shown by the use of TRAF-2 and TRAF-3 dominant-negative constructs. These data indicate that the activation of both the NF-κB and AP-1 pathways by LMP-1, CTAR-1, and CTAR-2 is necessary for the activation of MMP-9 expression. In NPC, LMP-1 may contribute to invasiveness and metastasis through the induction of MMP-9 transcription and enzymatic activity.

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The expression of matrix metalloproteinase 9 is enhanced by Epstein-Barr virus latent membrane protein 1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.7.3621 ◽

1998 ◽

Vol 95 (7) ◽

pp. 3621-3626 ◽

Cited By ~ 161

Author(s):

T. Yoshizaki ◽

H. Sato ◽

M. Furukawa ◽

J. S. Pagano

Keyword(s):

Membrane Protein ◽

Matrix Metalloproteinase ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Matrix Metalloproteinase 9 ◽

Latent Membrane Protein 1 ◽

Barr Virus ◽

Epstein Barr ◽

Virus Latent Membrane Protein ◽

Metalloproteinase 9

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Korelasi ekspresi LMP-1 dengan ekspresi E-chaderin dan MMP-9 pada mekanisme metastasis penderita KNF WHO tipe 3

Oto Rhino Laryngologica Indonesiana ◽

10.32637/orli.v49i1.263 ◽

2019 ◽

Vol 49 (1) ◽

pp. 40

Author(s):

Adrian Benediktus ◽

Soehartono Soehartono ◽

Hendradi Surjotomo

Keyword(s):

Statistical Analysis ◽

Matrix Metalloproteinase ◽

Epstein Barr Virus ◽

Significant Positive Correlation ◽

Significant Negative Correlation ◽

Barr Virus ◽

Epstein Barr ◽

Type 3 ◽

Metalloproteinase 9 ◽

E Cadherin

Latar belakang: Karsinoma nasofaring (KNF) adalah karsinoma sel skuamosa yang berasal dari epitel nasofaring. Salah satu etiologi KNF adalah infeksi Epstein-Barr virus (EBV). Pada biopsi jaringan KNF sering ditemukan genom EBV. Latent membran protein-1 (LMP-1) merupakan antigen dari EBV diekspresikan pada 65% KNF. Efek LMP-1 pada signaling salah satunya adalah memodulasi E-cadherin dan matrix metalloproteinase 9 (MMP-9) yang berperan pada proses metastasis. Metastasis adalah suatu proses yang kompleks dimana sel-sel kanker meninggalkan lokasi primer dan bermigrasi ke jaringan lain dalam tubuh. E-cadherin berfungsi sebagai mediator utama yang berperan terhadap adhesi sel-sel pada jaringan epitel, sedangkan MMP-9 menyebabkan rusaknya integritas dari matriks ekstraseluler yang merupakan barrier, sehingga memungkinkan sel tumor menginvasi jaringan sekitarnya. Tujuan: Untuk mengetahui korelasi ekspresi LMP-1 dengan ekspresi E-cadherin dan MMP-9 pada penderita KNF WHO tipe 3. Metode: Penelitian observasional analitik dengan desain potong lintang yang melibatkan 11 penderita KNF WHO tipe 3. Pemeriksaan ekspresi LMP-1, MMP-9, dan E-cadherin menggunakan metode pewarnaan imunohistokimia, dan hasilnya dihitung dengan menggunakan software ImmunoRatio. Hasil: Analisis statistik ekspresi LMP-1 dan E-cadherin menunjukkan korelasi negatif yang signifikan (p=0,000) dengan koefisien korelasi r= -0,940 (terdapat korelasi yang sangat kuat). Analisis korelasi ekspresi LMP-1 dan MMP-9 menunjukkan korelasi positif yang signifikan (p=0,000) dengan koefisien korelasi r=0,881 (terdapat korelasi yang sangat kuat). Kesimpulan: Semakin tinggi ekspresi LMP-1, maka ekspresi E-cadherin pada jaringan nasofaring penderita KNF WHO tipe 3 semakin menurun. Semakin tinggi ekspresi LMP-1 maka ekspresi MMP-9 pada jaringan nasofaring penderita KNF WHO tipe 3 semakin meningkat. Background: Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from nasopharynx epithel cells. Epstein-Barr virus (EBV) is one of the risk factor of NPC. EBV can often be found in NPC tissue biopsy. Latent membran protein 1 (LMP-1) is an antigen from EBV which is expressed in 65% of NPC. The effect of LMP-1 includes modifying E-cadherin and matrix metalloproteinase 9 (MMP-9) which important in metastasis. Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other tissues. E-cadherin is a main mediator in adhesion between cells. Decreased of E-cadherin makes tumor cells tend to migrate to other tissues of the body. MMP-9 involved in degradation of collagen IV in basement membranes and extracellular matrix facilitating invasion, metastasis, growth, and angiogenesis. Purpose: To determine the correlation between LMP-1 with E-cadherin and MMP-9 in WHO type 3 nasopharygeal carcinoma. Method: Observational analytic study with cross sectional design involving 11 NPC patients. The expression of LMP-1, E-cadherin, and MMP-9 using immunohistochemistry staining, and the results were calculated with ImmunoRatio software. Result: Statistical analysis showed significant negative correlation between LMP-1 dan E-cadherin (p=0.000) with r= -0.940 (very strong correlation). Statistical analysis showed significant positive correlation between LMP-1 dan MMP-9 (p=0.000) with r= 0.881 (very strong correlation). Conclusion: There was a significant negative correlation between LMP-1 dan E-cadherin in tissue from type 3 NPC patient. There was a significant positive correlation between LMP-1 dan MMP- 9 in tissue from type 3 NPC patient.

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Epstein–Barr Virus (EBV) Viral Load in Tumor Cells Did Not Predict Tumor Extensiveness in Nasopharyngeal Cancer

Microbiology Research ◽

10.3390/microbiolres12010011 ◽

2021 ◽

Vol 12 (1) ◽

pp. 150-156

Author(s):

Soehartati A. Gondhowiardjo ◽

Handoko ◽

Marlinda Adham ◽

Lisnawati Rachmadi ◽

Henry Kodrat ◽

...

Keyword(s):

Viral Load ◽

Tumor Cells ◽

Epstein Barr Virus ◽

Tumor Volume ◽

Nasopharyngeal Cancer ◽

Dna Quantification ◽

Barr Virus ◽

Nasopharyngeal Biopsy ◽

Ebv Dna ◽

Epstein Barr

Background: Nasopharyngeal cancer is commonly associated with Epstein–Barr virus (EBV) infection, especially undifferentiated non-keratinized histology. EBV DNA quantification through nasopharyngeal brushing was previously reported to be not related to disease stage. This study aimed to reinvestigate the relationship of EBV viral load in tumor tissue with tumor extensiveness by more accurate EBV DNA quantification through microscopically confirmed tumor cells from nasopharyngeal biopsy. Method: The specimens for EBV DNA quantification were derived from histopathology slides which were pre-treated following the QIAsymphony® SP protocol for tissue DNA extraction. Then, the extracted DNA underwent real-time polymerase chain reaction (RT-PCR) using the artus® EBV RG PCR Kit for EBV DNA quantification. The tumor volume was determined by delineating the gross tumor based on 3D imaging of the patient’s nasopharynx. Result: Twenty-four subjects were included in this study. All subjects were stage III and above, with more males (75%) than females. EBV viral load in tumor cells was found to have no correlation to tumor volume both in local and nodal regions. The median local tumor volume was 81.3 cm3 ± 80 cm3. The median EBV viral load in tumor cells was 95,644.8 ± 224,758.4 copies/100 ng of DNA. The median nodal or regional tumor volume was 35.7 ± 73.63 cm3. Conclusion: EBV viral load from tumor cells from nasopharyngeal biopsy has no relationship with tumor extensiveness in nasopharyngeal cancer. The presence and amount of EBV in tumor cells did not translate into larger or smaller tumors. The EBV viral proteins and RNAs were perhaps more likely to confer some prognostic information due to the fact that those molecules were related to carcinogenesis.

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