scholarly journals The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 127
Author(s):  
Adelaide Ohui Fierti ◽  
Michael Bright Yakass ◽  
Ernest Adjei Okertchiri ◽  
Samuel Mawuli Adadey ◽  
Osbourne Quaye
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Epstein Barr Virus ◽  
Epigenetic Silencing ◽  
Gene Products ◽  
Suppressor Genes ◽  
Barr Virus ◽  
Tumor Suppressor Proteins ◽  
Epstein Barr

Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.

The viruses in the human oncogénesis

Infectio ◽  
2018 ◽  
Vol 22 (4) ◽  
pp. 213
Author(s):  
Anggi Vélez-Bohórquez ◽  
Mabel Bohórquez-Lozano ◽  
Magdalena Echeverry-de-Polanco
Keyword(s):  
Tumor Suppressor ◽  
Hepatitis B ◽  
Tumor Suppressor Genes ◽  
Epstein Barr Virus ◽  
Oncogenic Potential ◽  
Barr Virus ◽  
Determining Factors ◽  
Oncogene Activation ◽  
Epstein Barr

Based on epidemiological associations and experimentation, relationships between viruses and cancer have been established. For more than 14 million new cases of cancer per year, it is estimated that 15% are related to viral agents. Epithelial, hematolymphoid and mesenchymal malignancies related to different viruses have been document such as Epstein Barr, Kaposi’s sarcoma, hepatitis B and C, human lymphotropic type 1, Merkel’s carcinoma and human papilloma. New virus with oncogenic potential such as cytomegalovirus, JC polyoma virus and BK have been described. The interaction of the viruses with the host induces oncogene activation, inhibition of tumor suppressor genes and activation of miRNAs, as determining factors in the development of cancer. The pathology is initiated with the infection that induces the deregulation of cell signaling. The Epstein Barr virus is the oncogenic prototype, with 1% of the human cancers related to it.

scholarly journals Tumor Suppressor p53 Stimulates the Expression of Epstein-Barr Virus Latent Membrane Protein 1

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Qianli Wang ◽  
Amy Lingel ◽  
Vicki Geiser ◽  
Zachary Kwapnoski ◽  
Luwen Zhang
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Tumor Suppressor P53 ◽  
Viral Oncogene ◽  
Barr Virus ◽  
Lmp1 Expression ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with multiple human malignancies. EBV latent membrane protein 1 (LMP1) is required for the efficient transformation of primary B lymphocytes in vitro and possibly in vivo. The tumor suppressor p53 plays a seminal role in cancer development. In some EBV-associated cancers, p53 tends to be wild type and overly expressed; however, the effects of p53 on LMP1 expression is not clear. We find LMP1 expression to be associated with p53 expression in EBV-transformed cells under physiological and DNA damaging conditions. DNA damage stimulates LMP1 expression, and p53 is required for the stimulation. Ectopic p53 stimulates endogenous LMP1 expression. Moreover, endogenous LMP1 blocks DNA damage-mediated apoptosis. Regarding the mechanism of p53-mediated LMP1 expression, we find that interferon regulatory factor 5 (IRF5), a direct target of p53, is associated with both p53 and LMP1. IRF5 binds to and activates a LMP1 promoter reporter construct. Ectopic IRF5 increases the expression of LMP1, while knockdown of IRF5 leads to reduction of LMP1. Furthermore, LMP1 blocks IRF5-mediated apoptosis in EBV-infected cells. All of the data suggest that cellular p53 stimulates viral LMP1 expression, and IRF5 may be one of the factors for p53-mediated LMP1 stimulation. LMP1 may subsequently block DNA damage- and IRF5-mediated apoptosis for the benefits of EBV. The mutual regulation between p53 and LMP1 may play an important role in EBV infection and latency and its related cancers. IMPORTANCE The tumor suppressor p53 is a critical cellular protein in response to various stresses and dictates cells for various responses, including apoptosis. This work suggests that an Epstein-Bar virus (EBV) principal viral oncogene is activated by cellular p53. The viral oncogene blocks p53-mediated adverse effects during viral infection and transformation. Therefore, the induction of the viral oncogene by p53 provides a means for the virus to cope with infection and DNA damage-mediated cellular stresses. This seems to be the first report that p53 activates a viral oncogene; therefore, the discovery would be interesting to a broad readership from the fields of oncology to virology.

Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16197-e16197
Author(s):  
Oleg I. Kit ◽  
Vladimir S. Trifanov ◽  
Natalya N. Timoshkina ◽  
Dmitry Yu. Gvaldin ◽  
Milana Yu. Mesheryakova ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Blood Levels ◽  
Malignant Neoplasms ◽  
Gene Promoters ◽  
Suppressor Genes ◽  
Healthy Donors ◽  
Pancreatic Net

e16197 Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.

scholarly journals Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4949-4958 ◽  
Author(s):  
A Hangaishi ◽  
S Ogawa ◽  
N Imamura ◽  
S Miyawaki ◽  
Y Miura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
Negative Regulators ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Lymphoid Malignancies ◽  
Cell Cycle Machinery

It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 have been shown to be consistently involved in the development of human cancers as tumor suppressors: Rb (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in human cancers, including leukemias/lymphomas. To address this point, we examined inactivations of these four genes in primary lymphoid malignancies by Southern blot and polymerase chain reaction-single- strand conformation polymorphism analyses. We also analyzed Rb protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all four tumor suppressors had one or more abnormalities of these four tumor-suppressor genes, indicating that dysregulation of cell cycle control is important for tumor development. Statistical analysis of interrelations among impairments of these four genes indicated that inactivations of the individual tumor-suppressor genes might occur almost independently. In some patients, disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53 inactivations. It is suggested that disruptions of multiple tumor suppressors in a tumor cell confer an additional growth advantage on the tumor.

scholarly journals Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

Blood ◽  
2016 ◽  
Vol 128 (13) ◽  
pp. 1735-1744 ◽  
Author(s):  
Niels Weinhold ◽  
Cody Ashby ◽  
Leo Rasche ◽  
Shweta S. Chavan ◽  
Caleb Stein ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Clonal Selection ◽  
Therapeutic Approaches ◽  
Apoptosis Resistance ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Key Points

Key PointsHits in driver genes and bi-allelic events affecting tumor suppressors increase apoptosis resistance and proliferation rate–driving relapse. Excessive biallelic inactivation of tumor suppressors in high-risk cases highlights the need for TP53-independent therapeutic approaches.

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