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Xi-Wen Bi, Hua Wang, Wen-Wen Zhang, Jing-Hua Wang, Wen-Jian Liu, Zhong-Jun Xia, Hui-Qiang Huang, Wen-Qi Jiang, Yu-Jing Zhang, Liang Wang
BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. METHODS: Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively...
October 13, 2016: Journal of Hematology & Oncology
Shotaro Ando, Jun-Ichi Kawada, Takahiro Watanabe, Michio Suzuki, Yoshitaka Sato, Yuka Torii, Masato Asai, Fumi Goshima, Takayuki Murata, Norio Shimizu, Yoshinori Ito, Hiroshi Kimura
Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model...
October 8, 2016: Oncotarget
Amber Shatzer, Mir A Ali, Mayra Chavez, Kennichi Dowdell, Min-Jung Lee, Yusuke Tomita, Iman El-Hariry, Jane B Trepel, David A Proia, Jeffrey I Cohen
HSP90 inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line...
August 11, 2016: Leukemia & Lymphoma
Ezequiel M Fuentes-Pananá, Abigail Morales-Sánchez
EBV-associated Gastric Cancer (EBVaGC) comprises about 9% of all cases of GC and constitutes a distinct clinicopathological and molecular entity. The pattern of viral expression in EBVaGC cannot be set to any of the previously EBV-associated malignancies. Several lines of evidence support that viral expression in EBVaGC is characterized by high transcription of the BamH1-A rightward transcript (BART), low-levels of EBNA-1 and lack of LMP1. The high transcription activity of the BamH1-A region is importantly directed to express BART miRNAs, supporting a critical role for these miRNAs during epithelial cell infection and carcinogenesis...
September 26, 2016: Current Cancer Drug Targets
Li Zhang, Na Li, Li Yang, Jing Zhang, Hua-Wei Weng, Li-Qun Zou
B-cell activating factor (BAFF) plays important roles in a variety of lymphoid malignancies. Compared with healthy adults, patients with non-Hodgkin lymphoma had higher level of serum BAFF, and it corresponded with disease severity, response for therapy and clinical outcome. Latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus (EBV) which is a known agent of nasal, extranodal NK/T cell lymphoma (ENKTCL) can switch the BAFF activating promoter leading to higher expression of BAFF in EBV-related tumor cells...
December 2016: Cytokine
Nihel Ammous-Boukhris, Amor Mosbah, Emna Sahli, Wajdi Ayadi, Boutheina Hadhri-Guiga, Ameur Chérif, Ali Gargouri, Raja Mokdad-Gargouri
Latent membrane protein 1 (LMP1), a major oncoprotein of Epstein Barr Virus (EBV) is responsible for transforming B lymphocytes in vitro. LMP1 is overexpressed in several EBV-associated malignancies, and different approaches have been developed to reduce its level and accordingly its oncogenic function in tumor tissues. This study aimed to use phage display peptide library to obtain peptides which could specifically bind to the cytoplasmic region of LMP1 to prevent its interaction with signaling proteins. The LMP1 C-terminus region was produced in bacterial E...
September 17, 2016: Peptides
Kung-Chao Chang, Paul Chih-Hsueh Chen, Yao Chang, Yu-Hsuan Wu, Ya-Ping Chen, Chien-Hsien Lai, L Jeffrey Medeiros, Ih-Jen Su, Hsei-Wei Wang
AIMS: Previously, we reported an association between Epstein-Barr virus (EBV)-positive Hodgkin lymphoma (HL), older age and poorer prognosis. The mechanisms underlying this association remain unclear. METHODS AND RESULTS: Transfection of HL cell lines with EBV-latent membrane protein-1 (LMP1) resulted in upregulation of many cytokine genes as assessed by using oligonucleotide microarrays. Three upregulated cytokines, were validated by using an inflammatory cytokine protein array: MIP-1α, MIP-1β, IL-13...
September 16, 2016: Histopathology
Alina Nicolae, Karthik A Ganapathi, Trinh Hoc-Tran Pham, Liqiang Xi, Carlos A Torres-Cabala, Nahid M Nanaji, Hongbin D Zha, Zhen Fan, Sybil Irwin, Stefania Pittaluga, Mark Raffeld, Elaine S Jaffe
Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with Epstein-Barr virus (EBV). Rare cases of EBV-negative ANKL have been described, and some reports suggested more indolent behavior. We report the clinicopathologic, immunophenotypic, and molecular characteristics of 7 EBV-negative ANKL. All patients were adults, with a median age of 63 years (range 22 to 83 y) and an M:F ratio of 2.5:1. Five patients were White, 1 Black, and 1 Asian. All patients presented acutely, with fever (6/7), cytopenias (6/7), and splenomegaly (4/7)...
September 14, 2016: American Journal of Surgical Pathology
Octavia Ramayanti, Hedy Juwana, Sandra A M W Verkuijlen, Marlinda Adham, Michiel D Pegtel, Astrid E Greijer, Jaap M Middeldorp
Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein-Barr virus (EBV) as oncogenic driver. NPC is often diagnosed late due to initial vague complaints and obscured location. Prior studies suggest that measurement of EBV DNA load and RNA transcripts in nasopharyngeal (NP) brushings is useful for minimally invasive NPC diagnosis. However, whether these EBV markers relate to local virus replication or reflect tumor origin remains to be demonstrated. To resolve this, we analysed EBV-DNA characteristics and quantified latent and lytic viral RNA transcripts in NP brushings and matching frozen NP-biopsy specimens from patients suspected of having NPC...
September 7, 2016: International Journal of Cancer. Journal International du Cancer
Wei-Wen Sung, Yi-Chih Chu, Peir-Rong Chen, Ming-Hui Liao, Jeng-Woei Lee
Latent membrane protein 1 (LMP1) is a pivotal viral oncoprotein that contributes to the carcinogenesis of Epstein-Barr virus (EBV)-associated malignancies, including nasopharyngeal carcinoma (NPC). We investigated the regulation of hypoxia-inducible factor 1-α (HIF-1α) by LMP1. In NPC cells, we found that LMP1 significantly enhanced the HIF-1α mRNA level, and not only the protein amount as described previously. Mechanistically, the stability of the HIF-1α transcript was remarkably prolonged by LMP1 via reduced expressions of RNA-destabilizing proteins tristetraprolin (TTP) and pumilio RNA-binding family member 2 (PUM2) through C-terminal activation region 1 (CTAR1) and CTAR3 interaction with the ERK1/2 and STAT3 signaling pathways, respectively, in parallel with hindrance of PUM2 binding to the HIF-1α mRNA 3'-untranslated region (3'-UTR)...
November 1, 2016: Cancer Letters
Mark N Jabbour, Samer Nassif, Zaher Chakhachiro
The presence of CD30-expressing Hodgkin-like cells with a background of inflammation and eosinophils in a young adolescent is usually diagnostic of classical Hodgkin lymphoma. Herein we present the case of a 12-year-old boy presenting with enlarged cervical lymph node characterized by the presence of Hodgkin-like cells expressing CD30 and EBV-LMP1 with a Hodgkin-like background. The Hodgkin-like cells were negative for CD15, CD20, CD45, and Pax-5. The tumor cells, however, expressed several cytokeratins, confirming the diagnosis of an undifferentiated carcinoma nasopharyngeal type...
August 19, 2016: International Journal of Surgical Pathology
Parikhit Borthakur, Kangkana Kataki, Chenole Keppen, V Khamo, Subhash Medhi, Manab Deka
BACKGROUND: Nasopharyngeal carcinoma (NPC), a malignancy arising from the epithelial lining of the nasopharynx, is distinct from others cancers in terms of its epidemiologic features. It is rare in most parts of the world except for a few regions with populations of Mongoloid origin. OBJECTIVES: To study the expression pattern of Epstein Barr virus (EBV) encoded oncoproteins EBNA1 and LMP1 in different histological types of NPC and to correlate expression patterns with sex, age and histological types...
2016: Asian Pacific Journal of Cancer Prevention: APJCP
Deilson Elgui de Oliveira, Cleiton Silva Marques, Victor Costa Losi
Comment on: J. Wei, J. Zhang, Y. Si, M. Kanada, Z. Zhang, S. Terakawa, H. Watanabe, Blockage of LMP1-modulated store-operated Ca(2+) entry reduces metastatic potential in nasopharyngeal carcinoma cell, Cancer Lett. 360 (2015) 234-244. doi:10.1016/j.canlet.2015.02.032.
October 10, 2016: Cancer Letters
Kayla A Martin, Lena N Lupey, Italo Tempera
UNLABELLED: The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV replication during latency. In this study, we detail the mechanisms that drive cellular PARylation during latent EBV infection and the effects of PARylation on host gene expression and cellular function. EBV-infected B cells had higher PAR levels than EBV-negative B cells...
October 1, 2016: Journal of Virology
Antonia Pavlovic, Merica Glavina Durdov, Vesna Capkun, Jasminka Jakelic Pitesa, Maja Bozic Sakic
BACKGROUND Classical Hodgkin lymphoma (cHL) is characterized by sparse malignant Hodgkin and Reed-Sternberg cells dispersed in an inflammatory microenvironment. Immune evasion of malignant cells is partially due to the existence of a subpopulation of immunosuppressive regulatory T cells (Treg). The aim of this study was to analyze T cell composition in cHL with special emphasis on Treg in regard to Epstein-Barr virus (EBV) status, subtype, and patient age. MATERIAL AND METHODS The study included 102 patients with cHL diagnosed during a 12-year period...
2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Panagiotis T Diamantopoulos, Maria Sofotasiou, Zafiroula Georgoussi, Nefeli Giannakopoulou, Vasiliki Papadopoulou, Athanasios Galanopoulos, Elina Kontandreopoulou, Panagiotis Zervakis, Paschalina Pallaki, Fani Kalala, Marie-Christine Kyrtsonis, Aglaia Dimitrakopoulou, Theodoros Vassilakopoulos, Maria Angelopoulou, Nikolaos Spanakis, Nora-Athina Viniou
Signal transducer and activator of transcription (STAT) proteins have been intensively studied in hematologic malignancies, and the efficacy of agents against STATs in lymphomas is already under research. We investigated the expression of total STAT5 and STAT5b in peripheral blood samples of patients with chronic lymphocytic leukemia (CLL) in correlation with the presence of Epstein-Barr Virus (EBV) and its major oncoprotein (latent membrane protein 1, LMP1). The EBV load was measured in the peripheral blood by real-time PCR for the BXLF1 gene and the levels of LMP1 by PCR and ELISA...
September 2016: Cancer Medicine
Junko Mukohyama, Dai Iwakiri, Yoh Zen, Toru Mukohara, Hironobu Minami, Yoshihiro Kakeji, Yohei Shimono
Establishment of patient-derived tumor xenografts (PDXs) is hampered by lymphomagenesis mostly caused by the latently-infected Epstein-Barr virus (EBV) contained in patient cancer tissues. However, the character of patient tissues that result in lymphomagenesis after xenotransplantation is not elucidated. In this study, we analyzed the patient colorectal cancer (CRC) tissues and the PDXs established by their xenotransplantation. We found that 2 of 9 (22%) PDX tumors were EBV-associated human diffuse large B cell lymphoma which was formed by clonal proliferation of human B-cell lymphocytes, were strongly positive for EBER-ISH, and were classified as type III latency...
June 29, 2016: Oncotarget
Ya-Chi Huang, Sue-Jane Lin, Kai-Min Lin, Ya-Ching Chou, Chung-Wu Lin, Shan-Chi Yu, Chi-Long Chen, Tang-Long Shen, Chi-Kuan Chen, Jean Lu, Mei-Ru Chen, Ching-Hwa Tsai
Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear...
September 22, 2016: Blood
Hai Hu, Man-Li Luo, Christine Desmedt, Sheida Nabavi, Sina Yadegarynia, Alex Hong, Panagiotis A Konstantinopoulos, Edward Gabrielson, Rebecca Hines-Boykin, German Pihan, Xin Yuan, Christos Sotirious, Dirk P Dittmer, Joyce D Fingeroth, Gerburg M Wulf
Whether the human tumor virus, Epstein-Barr Virus (EBV), promotes breast cancer remains controversial and a potential mechanism has remained elusive. Here we show that EBV can infect primary mammary epithelial cells (MECs) that express the receptor CD21. EBV infection leads to the expansion of early MEC progenitor cells with a stem cell phenotype, activates MET signaling and enforces a differentiation block. When MECs were implanted as xenografts, EBV infection cooperated with activated Ras and accelerated the formation of breast cancer...
July 2016: EBioMedicine
Shu Yang, Shi-Sheng Li, Xin-Ming Yang, Dan-Hui Yin, Lin Wang
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in the majority of tumor cells, whilst sparing normal cells. However, the potential use of TRAIL in the treatment of cancer is limited by the inevitable emergence of drug resistance. The present study reports the upregulation of latent membrane protein 1 (LMP1)-induced TRAIL resistance via the enhanced expression of X-linked inhibitor of apoptosis protein (XIAP) in nasopharyngeal carcinoma (NPC) cells. LMP1-positive NPC cells were indicated to be more sensitive to TRAIL compared with LMP1-negative NPC cells in three NPC cell lines...
June 2016: Oncology Letters
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