RESUMEN
Aberrant expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Gα13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor.
Asunto(s)
Factores de Transcripción Forkhead/fisiología , Linfoma de Células B Grandes Difuso/patología , Proteínas de Neoplasias/fisiología , Receptores de Lisoesfingolípidos/fisiología , Proteínas Represoras/fisiología , Transducción de Señal/fisiología , Animales , Apoptosis/fisiología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Factores de Transcripción Forkhead/genética , Subunidades alfa de la Proteína de Unión al GTP G12-G13/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Centro Germinal/patología , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Ratones , Trasplante de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-akt/análisis , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptores de Lisoesfingolípidos/biosíntesis , Receptores de Lisoesfingolípidos/deficiencia , Receptores de Lisoesfingolípidos/genética , Proteínas Represoras/genética , Receptores de Esfingosina-1-FosfatoRESUMEN
microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functions in post-transcriptional gene expression control. Many miRNAs are located in genomic regions that are frequently deleted in cancer, or are subject to epigenetic and transcriptional deregulation in cancer cells. The miRNA transcriptome of cancer cells is very different from that of their normal cell counterparts. miRNAs can exhibit oncogenic or tumor suppressive or even both properties depending on the specific targets and cellular context. It is becoming increasingly clear that miRNAs not only serve as useful tumor biomarkers with implications for diagnosis, prognosis and the prediction of treatment responses, but may also be used for targeted cancer treatment and even as therapeutics. In this review, we provide an overview of recent advances in our understanding of the tumor suppressor miRNAs and oncomiRs involved in the pathogenesis of leukemias and lymphomas, and their target transcripts in cancer signaling networks. In particular, we focus on the role of miRNAs in chronic lymphocytic and acute lymphoblastic leukemia and in B-cell lymphomas. In the second part, we review the various alternative strategies of targeting miRNAs in cancer therapy. Methods of oncomiR antagonization by antagomiRs or locked nucleid acids are contrasted with strategies that harness the tumor suppressive properties of certain miRNAs for cancer treatment. Preclinical progress, also with regard to delivery strategies, possible side effects and other pharmacological aspects, is presented along with results from the first human trials assessing the safety and efficacy of miRNA-targeting therapeutics.
