RESUMEN
Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL). To identify a molecular signature characteristic of MF tumor stage, we used a bioinformatic approach involving meta-analysis of publicly available gene expression data sets combined with previously generated gene expression data. Results for a selection of genes were further refined and validated by quantitative PCR and inclusion of additional controls. With this approach, we identified a profile specific for MF tumor stage, consisting of 989 aberrantly expressed genes, the majority of which (718 genes) are statistically significantly more expressed in MF compared with normal skin, inflamed skin, and normal T cells. As expected, the signature contains genes reflecting the highly proliferative characteristic of this T-cell malignancy, including altered expression of cell cycle and kinetochore regulators. We uncovered details of the immunophenotype, suggesting that MF originates from IL-32-producing cells and identified previously unreported therapeutic targets and/or diagnostic markers, for example, GTSF1 and TRIP13. Loss of expression of the NF-κB inhibitor, NFKBIZ, may partly explain the enhanced activity of NF-κB, which is a hallmark of MF and other CTCLs.
Asunto(s)
Proteínas Portadoras/biosíntesis , Perfilación de la Expresión Génica , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/metabolismo , Micosis Fungoide/genética , Micosis Fungoide/metabolismo , Proteínas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas , Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Biología Computacional/métodos , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas I-kappa B , Inmunofenotipificación , Interleucinas/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Modelos Genéticos , FN-kappa B/metabolismo , Proteínas Nucleares/biosíntesis , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas/genética , ARN Mensajero/metabolismoRESUMEN
The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes the constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-kappaB, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2. Finally, the involvement of COX-2 in US28-mediated tumor formation was evaluated using the COX-2 selective inhibitor Celecoxib. Targeting COX-2 in vivo with Celecoxib led to a marked delay in the onset of tumor formation in nude mice injected with US28-transfected NIH-3T3 cells and a reduction of subsequent growth by repressing the US28-induced angiogenic activity. Hence, the development of HCMV-related proliferative diseases may partially be ascribed to the ability of US28 to activate COX-2.