EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein⁻Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The relationship between Epstein-Barr virus (EBV) and the germinal centre (GC) of the asymptomatic host remains an enigma. The occasional appearance of EBV-positive germinal centres in some patients, particularly those with a history of immunosuppression, suggests that EBV numbers in the GC are subject to immune control. The relationship, if any, between lymphoid hyperplasia with EBV-positive germinal centres and subsequent or concurrent lymphomagenesis remains to be clarified. As far as the development of EBV-associated Hodgkin's lymphoma is concerned, the suppression of virus replication, mediated by LMP1 on the one hand, and the loss of B-cell receptor signalling on the other, appears to be an important pathogenic mechanism. A further important emerging concept is that alterations in the microenvironment of the EBV-infected B-cell may be important for lymphomagenesis.
- MeSH
- B-lymfocyty imunologie virologie MeSH
- buněčná diferenciace imunologie MeSH
- dospělí MeSH
- Hodgkinova nemoc imunologie virologie MeSH
- infekce virem Epsteina-Barrové virologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- proteiny virové matrix MeSH
- pseudolymfom virologie MeSH
- receptory antigenů B-buněk imunologie MeSH
- replikace viru imunologie MeSH
- virus Epsteinův-Barrové imunologie MeSH
- zárodečné centrum lymfatické uzliny imunologie virologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Publikační typ
- abstrakt z konference MeSH
BACKGROUND: Invasive ductal and lobular carcinomas (IDC and ILC) are the most common histological types of breast cancer. Clinical follow-up data and metastatic patterns suggest that the development and progression of these tumors are different. The aim of our study was to identify gene expression profiles of IDC and ILC in relation to normal breast epithelial cells. METHODS: We examined 30 samples (normal ductal and lobular cells from 10 patients, IDC cells from 5 patients, ILC cells from 5 patients) microdissected from cryosections of ten mastectomy specimens from postmenopausal patients. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. Samples were analysed upon Affymetrix U133 Plus 2.0 Arrays. The expression of seven differentially expressed genes (CDH1, EMP1, DDR1, DVL1, KRT5, KRT6, KRT17) was verified by immunohistochemistry on tissue microarrays. Expression of ASPN mRNA was validated by in situ hybridization on frozen sections, and CTHRC1, ASPN and COL3A1 were tested by PCR. RESULTS: Using GCOS pairwise comparison algorithm and rank products we have identified 84 named genes common to ILC versus normal cell types, 74 named genes common to IDC versus normal cell types, 78 named genes differentially expressed between normal ductal and lobular cells, and 28 named genes between IDC and ILC. Genes distinguishing between IDC and ILC are involved in epithelial-mesenchymal transition, TGF-beta and Wnt signaling. These changes were present in both tumor types but appeared to be more prominent in ILC. Immunohistochemistry for several novel markers (EMP1, DVL1, DDR1) distinguished large sets of IDC from ILC. CONCLUSION: IDC and ILC can be differentiated both at the gene and protein levels. In this study we report two candidate genes, asporin (ASPN) and collagen triple helix repeat containing 1 (CTHRC1) which might be significant in breast carcinogenesis. Besides E-cadherin, the proteins validated on tissue microarrays (EMP1, DVL1, DDR1) may represent novel immunohistochemical markers helpful in distinguishing between IDC and ILC. Further studies with larger sets of patients are needed to verify the gene expression profiles of various histological types of breast cancer in order to determine molecular subclassifications, prognosis and the optimum treatment strategies.
- MeSH
- biologické markery MeSH
- čipová analýza tkání metody MeSH
- duktální karcinom prsu genetika patologie MeSH
- extracelulární matrix - proteiny genetika MeSH
- financování organizované MeSH
- hybridizace in situ MeSH
- imunohistochemie MeSH
- kadheriny genetika MeSH
- kolagen typ III genetika MeSH
- lasery MeSH
- lidé MeSH
- lobulární karcinom genetika patologie MeSH
- mikrodisekce metody MeSH
- nádory prsu genetika patologie MeSH
- prsy metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
Léčba pokročilých stadií karcinomu prostaty představuje vážný medicínský problém. Vzhledem k vedlejším účinkům kastrace, jako jsou ztráta libida a impotence, se alternativou u některých pacientů s karcinomem prostaty stává monoterapie antiandrogeny. Dobrou snášenlivost, minimum vedlejších účinků a zachování sexuálních funkcí vykazuje především léčba bicalutamidem. Cílem této práce bylo shrnutí poznatků o molekulárních mechanizmech účinku tohoto antiandrogenu a diskutovat naše výsledky se zaměřením na aktivitu telomerázy, dráhu nádorového supresoru p53 a apoptózu. Zejména nový poznatek o aktivaci dráhy p53 a apoptózy vyššími dávkami bicalutamidu může vést k diskuzi o jejich zavedení do léčebné praxe u androgen senzitivních karcinomů. Vyšší dávky než 150 mg bicalutamidu denně se v současné klinické praxi nepoužívají, protože ve srovnání s kastrací nezpůsobují další pokles hladin prostatického specifického antigenu. Dávkování až 600 mg bicalutamidu denně je však pacienty dobře snášeno a vzhledem k diskutovaným účinkům bicalutamidu, by mohly vyšší dávky přinést zlepšení terapie androgen senzitivních karcinomů.
Androgen deprivation is currently the only effective systemic therapy available for metastatic prostate cancer. Monotherapy by antiandrogens represents for some patients an alternative to castration with respect to lower incidence of side effects. Advantages of antiandrogen bicalutamide include good tolerance, minimal side effects and retention of libido and sexual potency. We review the current knowledge on molecular mechanisms of bicalutamide action and discuss our results regarding telomerase activity, p53 pathway and apoptosis. In particular, the finding of activation of p53 pathway and apoptosis by higher doses of bicalutamide can lead to discussion on their usage in therapy of androgen sensitive carcinomas. Doses of bicalutamide higher than 150 mg daily are not clinically used now because they do not further decrease the levels of prostate specific antigen in comparison to castration. However, doses up to 600 mg daily are well tolerated and with respect to the discussed effects of bicalutamide, these higher doses of bicalutamide could be of bring benefit for patients with androgen sensitive carcinomas.
- MeSH
- antagonisté androgenů aplikace a dávkování farmakologie chemie MeSH
- apoptóza MeSH
- finanční podpora výzkumu jako téma MeSH
- karcinom farmakoterapie MeSH
- nádorový supresorový protein p53 MeSH
- nádory prostaty farmakoterapie MeSH
- regulace genové exprese MeSH
- telomerasa antagonisté a inhibitory MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
