GB and gH/gL fusion machinery: a promising target for vaccines to prevent Epstein-Barr virus infection.

Epstein‒Barr virus (EBV) is a double-stranded DNA virus belonging to the family Orthoherpesviridae that is associated with the development of various tumors, such as lymphoma, nasopharyngeal carcinoma, and gastric cancer. There are no uniformly effective treatments for human EBV infection, and vaccines and immunotherapies are currently the main research directions. The glycoproteins gB and gH/gL are surface glycoproteins that are common to all herpesviruses, with subtle differences in structure and function between different viruses. The core membrane fusion machinery constituted by EBV gB and gH/gL is an important target of neutralizing antibodies in epithelial EBV infection due to its essential role in the fusion of viral and target cell membranes. In this article, we review the main modes of EBV infection, the structure and function of the core fusion machinery gB and gH/gL, and the development of neutralizing antibodies and prophylactic vaccines based on this target.

Advances in the expression and function of Fyn in different human tumors

The tyrosine kinase Fyn is a member of the SRC family of kinases, and its sustained activation is closely linked to tumor cell migration, proliferation, and cell metabolism. Recently, Fyn has been found to be expressed in various tumor tissues, and the expression and function of Fyn vary between tumors, with Fyn acting as an oncogene to promote proliferation and metastasis in some tumors. This article summarizes the recent studies on the role of Fyn in different human tumors, focusing on the role of Fyn in melanoma, breast cancer, glioma, lung cancer, and peripheral T-cell lymphoma in order to provide a basis for future research and targeted therapy in different human tumors.(AU)

Mechanism of cisplatin resistance in gastric cancer and associated microRNAs.

Gastric cancer (GC) is a common malignant tumor with high morbidity and mortality rates that seriously affects human health worldwide. Although surgery is currently the preferred clinical treatment for GC, chemotherapy remains the first choice for perioperative treatment, adjuvant therapy, and palliative care for patients with advanced GC. Cisplatin (DDP) is an antineoplastic agent that has been used clinically for decades, and it is the first-line chemotherapy for many solid tumors. However, the therapeutic efficacy of DDP is often limited by resistance and the complexity of its resistance mechanisms, which involve multiple proteins and signaling pathways. It is well documented that a variety of microRNAs (miRNAs) differentially expressed in DDP-resistant GC cells play important roles in regulating or reversing DDP resistance via various pathways. In this review, we first provide an introduction to the cytotoxicity and major resistance mechanisms of DDP in GC and then discuss the role and mechanism of miRNAs in regulating the DDP resistance process in GC cells. This work demonstrates the potential of relevant miRNAs to become diagnostic and prognostic biomarkers for gastric cancer and targets of action to enhance chemosensitivity and provides directions for future research.

Advances in the expression and function of Fyn in different human tumors.

The tyrosine kinase Fyn is a member of the SRC family of kinases, and its sustained activation is closely linked to tumor cell migration, proliferation, and cell metabolism. Recently, Fyn has been found to be expressed in various tumor tissues, and the expression and function of Fyn vary between tumors, with Fyn acting as an oncogene to promote proliferation and metastasis in some tumors. This article summarizes the recent studies on the role of Fyn in different human tumors, focusing on the role of Fyn in melanoma, breast cancer, glioma, lung cancer, and peripheral T-cell lymphoma in order to provide a basis for future research and targeted therapy in different human tumors.

Role of Fyn in hematological malignancies.

BACKGROUND: Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and Fyn-C. Fyn-T is highly expressed in T lymphocytes, and its expression level is significantly higher in mature T cells than in immature T cells. The abnormal expression of Fyn is closely related to the metabolism, proliferation, and migration of tumor cells. Recent studies have shown that Fyn is expressed in a variety of tumor tissues, and its expression and function vary among different tumors. In some tumors, Fyn acts as a pro-oncogene to promote tumor proliferation and metastasis. Moreover, Fyn mutations have been detected in many hematological tumors in recent years, suggesting a critical regulatory role of Fyn in the development of malignancies. METHODS: This review analyzed the relevant literature in PubMed and other databases. PURPOSE: The aim of this study was to systemically review recent research findings on various aspects of Fyn in the pathogenesis and treatment of different types of hematological malignancies and suggests possible future research directions for targeted tumor therapy. CONCLUSION: Fyn could be a novel prognostic marker and therapeutic target. Treatment option targeting Fyn might be beneficial for future studies.

miR-4295 Promotes the Malignant Progression of Gastric Cancer via Targeting PTEN.

BACKGROUND: Gastric cancer (GC), one of the common clinical malignant tumors of the digestive system, is the fourth most commonly diagnosed cancer and the second lethal cancer worldwide and has the characteristics of high metastasis, fatality, and recurrence rate. This research was conducted to investigate the role and mechanism of miR-4295 in gastric cancer. METHODS: The expression capacity of miR-4295 was determined in gastric cancer tissues and its normal tissues by qRT-PCR. PTEN expression level was detected by western blot. SGC-7901 and MGC-803 cell lines were cultured and transfected with miR-4295 or its inhibitor. The effects of miR-4295 on cell proliferation, colony formation, migration, and invasion in vitro were investigated. The mutual effect between miR-4295 and PTEN in 293T cells was explored by luciferase reporter gene assays. RESULTS: The results showed that miR-4295 expression was higher in gastric cancer tissues and cell lines, and the miR-4295 level was significantly negatively associated with the tumor size and distal metastasis of gastric cancer. Notably, up-regulated miR-4295 promoted cell proliferation, migration and invasion in vitro, whereas it led to contrary effects while down-regulating miR-4295 expression. Further mechanism studies displayed that miR-4295 could directly fasten the PTEN 3'UTR and dramatically decrease the level of PTEN in vitro. CONCLUSION: The findings revealed that miR-4295 could promote gastric cancer cell proliferation, migration and invasion, which might be attributed to targeting PTEN. Our study suggested that miR-4295 might be a potential therapeutic target for gastric cancer.

TRIM65 in White Matter Lesions, Innate Immunity, and Tumor.

Most of the tripartite motif (TRIM) family proteins have E3 ubiquitin ligase activities and also have a variety of functions in cellular processes such as intracellular signal transduction, apoptosis, innate immunity, and carcinogenesis. TRIM65 is a member of the TRIM family. More pieces of evidence have shown a unique role and importance of TRIM65 protein in the occurrence and development of some diseases. In this review, the importance of TRIM65 in white matter lesions, innate immunity, and the effect of tumors were mainly reviewed.

Is there a CDKN2A-centric network in pancreatic ductal adenocarcinoma?

Pancreatic cancer has a high mortality rate and its incidence has risen rapidly in recent years. Meanwhile, the diagnosis and treatment of this cancer remain challenging. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, but, currently, no sufficiently effective modalities for its treatment exist. The early diagnosis rate of pancreatic cancer is low and most patients have reached an advanced stage at the time of diagnosis. PDAC evolves from precancerous lesions and is highly aggressive and metastatic. It is essential to understand how the disease progresses and metastasizes. CDKN2A mutations are very common in PDAC. Therefore, here, we have performed a literature review and discuss the role of CDKN2A and some related genes in the development of PDAC, as well as the basis of gene targeting with a correlation coefficient of CDKN2A above 0.9 on the STRING website. It is noteworthy that the interaction of CDKN2A with each gene has been reported in the literature. The role of these genes and CDKN2A in PDAC may provide new directions that will advance the current knowledge base and treatment options since cancer progression is realized through interactions among cells. Our findings provide new insights into the treatment of PADC that can, to some extent, improve the diagnosis rate and quality of life of patients.

shRNA targeting PLK1 inhibits the proliferation and invasion of nasopharyngeal carcinoma cells.

BACKGROUND: Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase, which has been studied as a potential gene therapy target for many years. PLK1 is overexpressed in a variety of tumors, and its expression often negatively correlated with patient prognosis. However, the role of PLK1 in nasopharyngeal carcinoma (NPC) is rarely studied. METHODS: Two recombinant vector plasmids were transfected into CNE2 cell lines by liposome transfection, CNE2/PLK1 shRNA target PLK1 mRNA, as well as a non-targeting control plasmid, CNE2/NC shRNA. Meanwhile, non-transfected cells (CNE2) were also used as controls. Real-time quantitative PCR (qRT-PCR) and Western blotting were performed to detect the transfection effect. The effects of the downregulation of PLK1 on cell biological behavior was evaluated in vitro by using CCK8, Transwell, colony-forming and flow-cytometry assays. RESULTS: PLK1 mRNA and protein were significantly inhibited in CNE2/PLK1 shRNA cells. Compared to control groups, the CNE2/PLK1 shRNA cells showed slower cell growth and a significantly decreased cell-cloning rate. Both migration and invasion were significantly inhibited in experimental cells. The proportions of G2-phase and apoptotic cells within the experimental group were significantly increased. CONCLUSIONS: Our results indicate that specific interference of PLK1 gene expression can significantly inhibit the proliferation and invasion of NPC (CNE2) cells.

Bioinformatic analysis of differentially expressed genes and identification of key genes in EBV-transformed lymphoblasts.

Although the Epstein-Barr virus (EBV) is a well-known human oncogenic virus, its molecular mechanisms involved in the transformation of healthy human cells remain poorly understood. In this study, human lymphocytes were isolated from the peripheral blood of healthy adults, and lymphocytes were transformed in vitro by EBV. Agilent human whole genome microarrays were used to detect the differential gene expression profiles of EBV-transformed lymphoblasts and healthy peripheral blood lymphocytes (PBLs). By constructing the gene functional network of EBV-induced lymphocyte transformation, we screened out candidate key genes in this process and verified their expression levels by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In the EBV-transformed lymphoblasts, 2335 differentially expressed genes, including 1328 up-regulated and 1007 down-regulated, were screened out. Five candidate key genes, namely, PLK1, E2F1, PTPN11, BIRC5 and FYN were mainly screened out according to the results of LIMMA, String, Cytoscape software analysis. RT-qPCR and Western blot showed that PLK1, E2F1, PTPN11, BIRC5 genes had increased expression levels, and FYN gene was down-regulated in EBV-transformed lymphoblasts. Silencing of PLK1 gene in Raji cells could inhibit cell proliferation and invasion, and induce cell cycle arrest and apoptosis. In conclusion, PLK1, E2F1, PTPN11, BIRC5 and FYN are the candidate key molecules of EBV-transformed lymphocytes.

Annexin A1 can inhibit the in vitro invasive ability of nasopharyngeal carcinoma cells possibly through Annexin A1/S100A9/Vimentin interaction.

Annexin A1 is a member of a large superfamily of glucocorticoid-regulated, calcium- and phospholipid-binding proteins. Our previous studies have shown that the abnormal expression of Annexin A1 is related to the occurrence and development of nasopharyngeal carcinoma (NPC). To understand the roles of Annexin A1 in the tumorigenesis of NPC, targeted proteomic analysis was performed on Annexin A1-associated proteins from NPC cells. We identified 436 proteins associated with Annexin A1, as well as two Annexin A1-interacted key proteins, S100A9 and Vimentin, which were confirmed by co-immunoprecipitation. Gene function classification revealed that the Annexin A1-associated proteins can be grouped into 21 clusters based on their molecular functions. Protein-protein interaction analysis indicated that Annexin A1 /S100A9/Vimentin interactions may be involved in the invasion and metastasis of NPC because they can form complexes in NPC cells. The down-regulation of Annexin A1 in NPC may lead to the overexpression of S100A9/Vimentin, which may increase the possibility of the invasion ability of NPC cells by adjusting the function of cytoskeleton proteins. Results suggested that the biological functions of Annexin A1 in NPC were diverse, and that Annexin A1 can inhibit the in vitro invasive ability of NPC cells through Annexin A1 /S100A9/Vimentin interaction.

Identification of IgH gene rearrangement and immunophenotype in an animal model of Epstein-Barr virus-associated lymphomas.

Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma. Because the susceptible hosts of EB virus are limited to human and cotton-top tamarins (Saguinus oedipus), there have been no appropriate animal models until the lymphoma model induced by EBV in human peripheral blood lymphocyte (hu-PBL)/SCID chimeric mice was reported. However, it is still controversial whether the EBV-associated lymphoma induced in hu-PBL/SCID mice is a monoclonal tumor. In this study, we transplanted normal human peripheral blood lymphocytes (hu-PBL) from six donors infected with EBV into SCID mice to construct hu-PBL/SCID chimeric mice. The induced tumors were found in the mediastinum or abdominal cavity of SCID mice. Microscopic observation exhibited tumor cells that were large and had a plasmablastic, centroblastic or immunoblastic-like appearance. Immunophenotyping assays showed the induced tumors were LCA-positive, CD20/CD79a-positive (markers of B cells), and CD3/CD45RO-negative (markers of T cells). A human-specific Alu sequence could be amplified by Alu-PCR. This confirmed that induced tumors were B-cell lymphomas originating from the transplanted human lymphocytes rather than mouse cells. EBER in situ hybridization detected positive signals in the nuclei of the tumor cells. Expression of EBV-encoded LMP1, EBNA-1, and EBNA-2 in the tumors was significantly positive. PCR-based capillary electrophoresis analysis of IgH gene rearrangement revealed a monoclonal peak and single amplification product in all six cases of induced tumors. This indicated that EBV can induce monoclonal proliferation of human B lymphocytes and promotes the development of lymphoma. J. Med. Virol. 88:1804-1813, 2016. © 2016 Wiley Periodicals, Inc.

Expression of LMP and EBNA genes in Epstein-Barr virus-associated lymphomas in Hu-PBL/SCID mice.

Transplantation of peripheral blood lymphocytes (PBLs) from healthy humans with latent Epstein-Barr virus (EBV) infection into severe combined immunodeficiency (SCID) mice results in development of EBV-associated human B-cell lymphoma. However, the expression of EBV genes in relation to lymphoma development has not been reported. We investigated latent membrane protein (LMP) and EBV nuclear antigen (EBNA) gene expression in PBLs from EBV-positive blood donors and induced-lymphoma cells from SCID mice to elucidate the functions and effects of the EBV genome in the occurrence and development of lymphoma. PBLs were isolated from 9 healthy blood donors and transplanted into SCID mice. Gene expression levels of LMP-1, LMP-2A, and LMP-2B and EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C and EBNA-LP were monitored by real-time quantitative-polymerase chain reaction (qRT-PCR) in cells from nine EBV-induced lymphomas and in matched lymphocytes from healthy subjects. LMP-1, EBNA-1 and EBNA-2 protein levels were detected by western blotting. As a result, LMP-1, LMP-2A and LMP-2B mRNA levels were upregulated 256-, 38- and 331-fold, respectively, in the EBV-induced lymphoma cells compared with the controls, while EBNA-1 and EBNA-3A mRNA levels were upregulated 1157- and 1154-fold, respectively. EBNA-2, EBNA-3B, EBNA-3C and EBNA-LP mRNAs were detected in lymphoma cells, but not in lymphocytes from EBV-positive blood donors. LMP-1 and EBNA-2 proteins were not expressed in lymphocytes from EBV-positive blood donors, according to western blotting. Weak EBNA-1 expression was observed in lymphocytes from blood donors with latent EBV infection, while LMP-1, EBNA-1 and EBNA-2 protein levels were significantly upregulated in EBV-induced lymphoma cells, consistent with mRNA expression levels detected by qRT-PCR. In conclusion, LMP-1, LMP-2A, LMP-2B, EBNA-1 and EBNA-3A were upregulated in EBV-induced lymphoma cells, while EBNA-2, EBNA-3B, EBNA-3C and EBNA-LP were absent in lymphocytes from humans with latent EBV infection, but were positively expressed in EBV-induced lymphoma cells.

The copy number of Epstein-Barr virus latent genome correlates with the oncogenicity by the activation level of LMP1 and NF-κB.

A tumor model that Epstein-Barr virus (EBV) latent infection facilitated the tumorigenicity was previously established using the Maxi-EBV system. In the present approach, EBV-lost cell clones demonstrated significantly decreased tumorigenesis. On the other hand, the LMP1 gene in Maxi-EBV genome was replaced by that of nasopharyngeal carcinoma origin. The resultant cell line, 293-1/NL showed much lower malignancy than the original 293-EBV. The result was opposite to our expectation. The change of 293 sublineage cells for EBV harboring also got similar result. To seek the underlying reason, the copy number of EBV genome in all the cell lines was detected. The result indicated that 293-EBV contained about 4.5-fold higher EBV copies than 293-1/NL did. Parallel EBV genomes led to relatively stable copies in different 293 sublineages, suggesting the viral genome structure is a factor for the sustainability of EBV's copy number. Moreover, the LMP1 transcription in high copy-containing cells showed abnormally high level. Furthermore, the main LMP1-driven pathway, transcription factor NF-κB, was highly activated in high-copy cells. Here we first manifest by experimental model that the copy number of EBV latent genome correlates with the viral pathogenesis, which depends on the activation level of LMP1 and NF-κB. Overall, both the presence and amount of EBV genome are crucial for the viral oncogenicity.

Expression of latent membrane proteins in Epstein­Barr virus-transformed lymphocytes in vitro.

Infection with Epstein-Barr virus (EBV) induces activation and proliferation of B lymphocytes. Detection of latent membrane protein (LMP)-1 is used to identify the proliferative ability of B cells. However, changes in the expression levels of the three LMPs during EBV-induced B lymphocyte transformation, have not yet been reported. In the present study, the expression levels of LMP-1, LMP-2A and LMP-2B were compared between EBV-transformed B lymphocytes and paired normal lymphocytes. Seven lymphoblast cell lines were established by EBV infection of normal human lymphocytes in vitro. The expression levels of LMP genes and LMP-1 protein were determined using quantitative (q)PCR and western blotting in lymphoblasts and normal lymphocytes, respectively. The expression of LMP1, LMP-2A and LMP-2B genes was significantly upregulated in EBV-induced lymphoblasts compared with the normal lymphocytes. The LMP-1 protein level was also significantly increased in EBV-transformed B lymphocytes. Expression of LMP1, LMP-2A and LMP-2B genes was significantly upregulated in EBV-induced lymphoblasts, suggesting LMP genes are important in the transformation of human lymphocytes.

Cloning and expression analysis of the gastric carcinoma-related gene, ELCOX3.

Gastric cancer is a pathological process of an accumulation of multigene and multistage mutations. A new gene segment, MDSCBC11, has been previously obtained using a gene chip and is negatively associated with gastric cancer. The present study aimed to clone the full cDNA sequence of the MDSCBC11 segment and to detect its expression in gastric carcinomas and normal gastric mucosa. Multiple-tissue northern blots revealed that the new MDSCBC11-represented gene was expressed as two transcripts that were 0.8 kb and 1.5 kb in size. The cDNA sequence of the smaller transcript was 822 bp, created by 5' rapid amplification of cDNA ends (RACE) and 3' RACE methods. A bioinformatics analysis indicated that the deduced amino acid sequence of MDSCBC11 had a 99% homology with the cytochrome c oxidase III (COX3) gene in the mitochondria. A total of 46 cases of gastric carcinomas, adjacent gastric mucosa and normal gastric mucosa were individually collected, and the mRNA expression of the ELCOX3 gene was detected by RT-PCR. ELCOX3 mRNA was expressed in all 46 cases of the normal gastric mucosa. The expression levels of ELCOX3 mRNA in the gastric carcinomas were lower compared with that of the adjacent and normal gastric mucosa (P<0.05), with the percent of downregulation at 23.91% (11/46 cases). The downregulation of ELCOX3 gene expression was associated with the development of human gastric carcinomas.

Screening and functional analysis of differentially expressed genes in EBV-transformed lymphoblasts.

BACKGROUND: Epstain-Barr virus (EBV) can transform human B lymphocytes making them immortalized and inducing tumorigenic ability in vitro, but the molecular mechanisms remain unclear. The aim of the present study is to detect and analyze differentially expressed genes in two types of host cells, normal human lymphocytes and coupled EBV-transformed lymphoblasts in vitro using gene chips, and to screen the key regulatory genes of lymphocyte transformation induced by EB virus. METHODS: Fresh peripheral blood samples from seven healthy donors were collected. EBV was used to transform lymphocytes in vitro. Total RNA was extracted from 7 cases of the normal lymphocytes and transformed lymphoblasts respectively, marked with dihydroxyfluorane after reverse transcription, then hybridized with 4 × 44 K Agilent human whole genome microarray. LIMMA, String, Cytoscape and other softwares were used to screen and analyze differentially expressed genes. Real-time PCR was applied to verify the result of gene expression microarrays. RESULTS: There were 1745 differentially expressed genes that had been screened, including 917 up-regulated genes and 828 down-regulated genes. According to the results of Generank, String and Cytoscape analyses, 38 genes may be key controlled genes related to EBV-transformed lymphocytes, including 22 up-regulated genes(PLK1, E2F1, AURKB, CDK2, PLCG2, CD80, PIK3R3, CDC20, CDC6, AURKA, CENPA, BUB1B, NUP37, MAD2L1, BIRC5, CDC25A, CCNB1, RPA3, HJURP, KIF2C, CDK1, CDCA8) and 16 down-regulated genes(FYN, CD3D, CD4, CD3G, ZAP70, FOS, HCK, CD247, PRKCQ, ITK, LCP2, CXCL1, CD8A, ITGB5, VAV3, CXCR4), which primarily control biological processes such as cell cycle, mitosis, cytokine-cytokine pathway, immunity response and so on. CONCLUSIONS: Human lymphocyte transformation induced by EB virus is a complicated process, involving multiple-genes and -pathways in virus-host interactions. Global gene expression profile analysis showed that EBV may transform human B lymphocytes by promoting cell cycle and mitosis, inhibiting cell apoptosis, hindering host immune function and secretion of cytokines.

Human-derived IgG level as an indicator for EBV-associated lymphoma model in Hu-PBL/SCID chimeras.

BACKGROUND: Epstein-Barr virus (EBV) has a close association with various types of human lymphomas. Animal models are essential to elucidate the pathogenesis of human EBV-associated lymphomas. The aim of the present study is to evaluate the association between human IgG concentration and EBV-associated lymphoma development in huPBL/SCID mice. METHODS: Human peripheral blood lymphocytes (hu-PBL) from EBV-seropositive donors were inoculated intraperitoneally into SCID mouse. Immunohistochemical staining was used to examine differentiated antigens of tumor cells. EBV infection of the induced tumors was detected by in situ hybridization. IgG concentrations in the serums of 12 SCID mice were measured by unidirectional immunodiffusion assay. RESULTS: 21 out of 29 mice developed tumors in their body. Immunohistochemical staining showed that all induced tumors were LCA (leukocyte common antigen) positive, B-cell markers (CD20, CD79a) positive, and T-cell markers (both CD3 and CD45RO) negative. The tumors can be diagnosed as human B-cell lymphomas by these morphological and immunohistochemical features. In situ hybridization exhibited resultant tumor cells had EBV encoded small RNA-1 (EBER-1). Human-derived IgG could be found in the serum from SCID mice on the 15th day following hu-PBL transplantation, and IgG levels increased with the tumor development in 6 hu-PBL/SCID chimeras. CONCLUSIONS: Intraperitoneal transfer of hu-PBLs from EBV+ donors to SCID mice leads to high human IgG levels in mouse serum and B cell lymphomas. Our findings suggest that increasing levels of human-derived IgG in peripheral blood from hu-PBL/SCID mice could be used to monitor EBV-related human B-cell lymphoma development in experimental animals.

Gene analysis of Epstein-Barr virus-associated lymphomas in Hu-Pbl/SCID chimeras.

AIMS AND BACKGROUND: The mechanisms of Epstein-Barr virus (EBV)-associated tumor development are incompletely understood. The aim of this study was to investigate the gene expression of EBV-associated lymphomas in hu-PBL/SCID mice. METHODS: Human peripheral blood lymphocytes (hu-PBL) from EBV-seropositive donors were transplanted into severe combined immunodeficiency (SCID) mice. In situ hybridization was used to detect EBV-encoded small RNA- 1 (EBER1) in tumor tissues. Mutation of TP53 exons 5-8 in EBV-induced lymphomas was analyzed by PCR-SSCP. Immunohistochemical staining was used to examine EBV gene products and cellular oncoproteins. RESULTS: Twenty-one of 29 mice developed tumors. EBER1 was positive in the nuclei of almost all tumor cells. Immunohistochemistry showed positive staining of LMP1, EBNA2 and ZEBRA in a small number of tumor cells. Immunohistochemically detectable p53 protein expression was common (85.7%), but TP53 gene mutations were identified in only four cases (19.1%) of EBV-associated lymphomas. Positivity rates of C-myc, Bcl-2 and Bax expression were 100%, 95.2%, and 90.5%, respectively, in the 21 cases of EBV-associated lymphomas. CONCLUSIONS: Our preliminary findings suggest that EBV-associated lymphomas in hu-PBL/SCID chimeras show EBV infection, expression of oncogenic viral genes, and overexpression of cellular oncogenes. TP53 gene mutations are rare but p53 protein is commonly expressed in EBV-associated lymphomas.

The prevalence of Epstein-Barr virus infection in different types and sites of lymphomas.

To analyze the association of several types of malignant lymphomas in different anatomical sites with the Epstein-Barr virus (EBV) infection status, 127 cases of formalin-fixed paraffin-embedded samples of malignant lymphomas were investigated with in situ hybridization detecting EBV-encoded small RNA (EBER) in tumor cells. Forty-six out of 108 non-Hodgkin lymphoma (NHL) cases were positive for EBER (42.6%). The EBER-positivity rate of NHL in the nasal cavity and nasopharynx (35/60 cases, 58.3%) was higher than that of NHL in stomach (9/30 cases, 30%) and in the superficial lymph nodes (2/18 cases, 11.1%) (P<0.05). The EBER-positivity rate of Hodgkin lymphoma in the superficial lymph nodes was 26.3% (5/19 cases). These findings suggest that the EBV-positivity rate in lymphomas is related to their histological types and locations.