Evaluation of LMP1 of Epstein-Barr virus as a therapeutic target by its inhibition
| Autor: | Adele Hannigan, Joanna B. Wilson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Herpesvirus 4 Human Cell Nasopharyngeal neoplasm Clone (cell biology) Mice Transgenic Biology medicine.disease_cause lcsh:RC254-282 Viral Matrix Proteins 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor medicine otorhinolaryngologic diseases Animals 030304 developmental biology 0303 health sciences Cell growth Research Nasopharyngeal Neoplasms lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Epstein–Barr virus Hodgkin Disease 3. Good health stomatognathic diseases medicine.anatomical_structure Nasopharyngeal carcinoma Oncology 030220 oncology & carcinogenesis Cancer cell Immunology Cancer research Molecular Medicine Carcinogenesis |
| Zdroj: | Molecular Cancer Molecular Cancer, Vol 9, Iss 1, p 184 (2010) |
| ISSN: | 1476-4598 |
| Popis: | Background The latent membrane protein-1 (LMP1) encoded by Epstein-Barr virus (EBV) is an oncoprotein which acts by constitutive activation of various signalling pathways, including NF-κB. In so doing it leads to deregulated cell growth intrinsic to the cancer cell as well as having extrinsic affects upon the tumour microenvironment. These properties and that it is a foreign antigen, lead to the proposition that LMP1 may be a good therapeutic target in the treatment of EBV associated disease. LMP1 is expressed in several EBV-associated malignancies, notably in Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). However, the viral protein is only detected in approximately 30%-50% of NPC samples, as such its role in carcinogenesis and tumour maintenance can be questioned and thus its relevance as a therapeutic target. Results In order to explore if LMP1 has a continuous function in established tumours, its activity was inhibited through expression of a dominant negative LMP1 mutant in tumour cell lines derived from transgenic mice. LMP1 is the tumour predisposing oncogene in two different series of transgenic mice which separately give rise to either B-cell lymphomas or carcinomas. Inhibition of LMP1 activity in the carcinoma cell lines lead to a reduction in clonagenicity and clone viability in all of the cell lines tested, even those with low or below detection levels of LMP1. Inhibition of LMP1 activity in the transgenic B-cell lines was incompatible with growth and survival of the cells and no clones expressing the dominant negative LMP1 mutant could be established. Conclusions LMP1 continues to provide a tumour cell growth function in cell lines established from LMP1 transgenic mouse tumours, of both B-cell and epithelial cell origin. LMP1 can perform this function, even when expressed at such low levels as to be undetectable, whereby evidence of its expression can only be inferred by its inhibition being detrimental to the growth of the cell. This raises the possibility that LMP1 still performs a pro-oncogenic function in the 50% to 70% of NPC tumours wherein LMP1 protein expression cannot be detected. This reinforces the basis for pursuing LMP1 as a therapeutic target in EBV associated LMP1-expressing malignancies. |
| Databáze: | OpenAIRE |
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