The early stage of oncogenesis is linked to the disorder of the cell cycle. Abnormal gene expression often leads to cell cycle disorders, resulting in malignant transformation of human cells. Epstein-Barr virus (EBV) is associated with a diverse range of human neoplasms, such as malignant lymphoma, nasopharyngeal carcinoma and gastric cancer. EBV mainly infects human lymphocytes and oropharyngeal epithelial cells. EBV is latent in lymphocytes for a long period of time, is detached from the cytoplasm by circular DNA, and can integrate into the chromosome of cells. EBV expresses a variety of latent genes during latent infection. The interaction between EBV latent genes and oncogenes leads to host cell cycle disturbances, including the promotion of G1/S phase transition and inhibition of cell apoptosis, thereby promoting the development of EBV-associated neoplasms. Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis involve diverse genes and signal pathways. Here, we review the molecular mechanisms of EBV-driven cell cycle progression and promoting oncogenesis.
MicroRNAs (miRNAs) are internal, non-coding, and ∼22 nt small RNAs that display cell- and tissue-specific expression. They play important regulatory roles in cell proliferation and chemo-sensitivity. This study focused on tumor-suppressive miR-33b-5p expression as well as its role in gastric cancer. MiR-33b-5p was found low expression in gastric cancer cell lines. Functionally, western blots and the luciferase reporter assay were used to confirm that HMGA2 was the potential target of miR-33b-5p. Next, we used CCK-8 kits to analyze the effect of miR-33b-5p combined chemotherapy drugs on cell inhibition rate, and flow cytometry to analyze cells apoptosis. Colony formation ability was determined by plating at 500 cells per well into six-well plates and culturing for 15 d. The results showed that upregulation of miR-33b-5p decreased expression of HMGA2 and inhibited gastric cancer cell growth as well as sensitized gastric cancer cells to chemotherapy drugs. MiR-33b-5p overexpression hindered luciferase activity of HMGA2,3'-untranslated region-based reporter construct in 293 T cells. These data demonstrate that miR-33b-5p may be a potential therapeutic target for gastric cancer and function as tumor-suppressive miRNA through targeting HMGA2 in gastric cancer.
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.
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.
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.
Peyton Rous established the scientific field of tumor virology in 1911 by discovering Rous sarcoma virus.In 1930s Richard identified mammalian tumor viruses,and the first human tumor virus-EBV was discovered in 1960s,and hepatitis B virus and the papillomaviruses then followed.The thorough research of tumor virus spurred the concept of oncogenes and the identification and function of tumor suppressor genes,and promoted the cancer vaccine research,which can inhibit virus infection and decrease tumor inci-dence.In the 1980s and 1990s,additional human tumor viruses——human T-cell leukemia virus type 1,hepatitis C virus,and Kaposi's sarco-ma herpesvirus were identified.Current estimates suggest that six kinds of viruses(EBV,HBV,HPV,HTLV-1,HCV,KSHV)are involved in 15% to 20% of human cancers worldwide.Thus,viruses not only have been shown to represent etiologic agents for many human can-cers but also have served as tools to reveal mechanisms that are involved in human malignancies.
Objective To detect the expression of Smad2 and Smad7 in cutaneous squamous cell carcinomas(SCC) and normal squamous epithelia of skins,analyze the relationship of two Smad expressions in SCC of differentiation grades and clinical stages,thus explore the role of Smad2 and Smad7 in the pathogenesis of SCC.Methods Paraffin-embedded tissue sections containing normal squamous epithelia,well differentiated,moderately differentiated and poorly differentiated SCC were stained by SABC immunohistochemistry technique to detect the expression and location of Smad2 and Smad7.Protein immunoexpression was quantified by image analysis in the context of histopathological parameters.The different expressions of Smad2 and Smad7 among all the tissue sections were compared.Expression of Smad2 and Smad7 in different clinical stages of SCC was also analyzed. Results Expression of Smad2 and Smad7 located in cytoplasm in normal squamous epithelia and SCC of skins.There was statistically significant difference of Smad2 and Smad7 expression between normal skin and SCC(P0.05).Compared with normal group,expression of Smad2 was down-regulated and Smad7 was up-regulated in SCC. Obvious difference of expression of Smad2 demonstrated in stage Ⅰ or Ⅱ compared with stage Ⅲ(P0.05).However,there was no statistic difference of Smad7 though gradually increasing from stage I to stage Ⅲ. Conclusions Down-regulation of Smad2 and up-regulation of Smad7 contribute to relieve the inhibition effect mediated by TGF β of cellular proliferation,which results in losing of cell growth suppression mediated by TGF β and contribute to tumor development or progression.Down-regulation of expression of Smad2,down-stream molecular of TGF β signaling pathway,was associated with invasion and metastasis of SCC.
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.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)