Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma.
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is a distinct subgroup of GC, comprising 10% of all cases of GC. EBV-associated carcinoma is the monoclonal growth of EBV-infected epithelial cells, and it represents a model of virus-host interactions leading to carcinoma. EBV-infected cells express several latent proteins (latency I program of viral latent gene expression) in EBV-associated GC. However, latent membrane protein 2A (LMP2A) up-regulates the cellular survivin gene through the NFkB pathway, conferring resistance to apoptotic stimuli on the neoplastic cells. EBV-associated GC also shows characteristic abnormality, that is, global and non-random CpG island methylation of the promoter region of many cancer-related genes. Since the viral genes are also regulated by promoter methylation in the infected cells, the DNA methylation mechanism specific to EBV-associated GC may be an exaggeration of the cellular mechanism, which is primarily for defense against foreign DNA. Production of several immunomodulator molecules, inducing tumor-infiltrating lymphocyte and macrophages, serves to form the characteristic histologic pattern in EBV-associated GC. The proposed sequence of events within the mucosa is as follows: EBV infection of certain gastric stem cells; expression of viral latent genes; abnormality of signal pathways caused by viral gene products; DNA methylation-mediated repression of tumor suppressor genes; and monoclonal growth of EBV-infected cells through interaction with other etiologic factors. Potentially useful therapeutic approaches to EBV-associated GC are those that utilize the virus-host interactions, such as bortezomib-induced and viral enzyme-targeted radiotherapy.
Fukayama
Masashi
M
Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. mfukayama-tky@umin.ac.jp
Hino
Rumi
R
Uozaki
Hiroshi
H
D004847:Epithelial Cells / Q000821:virology*; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000473:pathology; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology / Q000821:virology*; D000097782:NF-kappaB-Inducing Kinase
D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase