RESUMEN
We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin and Reed-Sternberg cells of cHL at higher levels than in non-Hodgkin lymphoma subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Here, we show that high FOXO3A levels in cHL reflect a B-cell-differentiation-specific pattern. In B cells, FOXO3A expression increases during the process of centroblast to plasma cell (PC) differentiation. FOXO3A levels in cHL were found higher than in germinal center B cells, but lower than in terminally differentiated PCs. This intermediate FOXO3A expression in cHL might manifest the "abortive PC differentiation" phenotype. This assumption was further corroborated by the finding that overexpression of FOXO3A in cHL cell lines induced activation of the master PC transcription factor PRDM1α. As factors attenuating FOXO3A expression in cHL, we identified MIR155 and constitutive activation of extracellular signal-regulated kinase. Finally, we demonstrate the importance of FOXO3A expression in cHL using an RNA interference approach. We conclude that tightly regulated expression of FOXO3A contributes to the oncogenic program and to the specific phenotype of cHL.
Asunto(s)
Diferenciación Celular , Proteína Forkhead Box O3/biosíntesis , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/metabolismo , Proteínas de Neoplasias/biosíntesis , Células Plasmáticas/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Proteína Forkhead Box O3/genética , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Células Plasmáticas/patología , ARN Neoplásico/genética , ARN Neoplásico/metabolismoRESUMEN
The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation. Here we show that FOXO1 directly upregulates the full-length isoform PRDM1α in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1α acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1α downregulation in cHL and identify PRDM1α as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Células Plasmáticas/patología , Proteínas Represoras/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Regulación hacia Abajo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Enfermedad de Hodgkin/metabolismo , Humanos , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-myc/metabolismo , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Proteínas Represoras/genética , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
The FOXO transcription factors control proliferation and apoptosis in different cell types. Their activity is regulated by posttranslational modifications, mainly by the PI3K-PKB pathway, which controls nuclear export and degradation. We show that FOXO1 is highly expressed in normal germinal center B cells as well as in non-Hodgkin lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue non-Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma. In contrast, in 31 of 32 classical Hodgkin lymphoma (cHL) cases, Hodgkin and Reed-Sternberg cells were FOXO1 negative. Neoplastic cells of nodular lymphocyte-predominant Hodgkin lymphoma were negative in 14 of 20 cases. FOXO1 was down-regulated in cHL cell lines, whereas it was expressed in non-Hodgkin lymphoma cell lines at levels comparable with normal B cells. Ectopic expression of a constitutively active FOXO1 induced apoptosis in cHL cell lines and blocked proliferation, accompanied with cell-cycle arrest in the G(0)/G(1) phase. We found that, in cHL cell lines, FOXO1 is inactivated by multiple mechanisms, including constitutive activation of AKT/PKB and MAPK/ERK kinases and up-regulation of microRNAs miR-96, miR-182, and miR-183. These results suggest that FOXO1 repression contributes to cHL lymphomagenesis.
Asunto(s)
Factores de Transcripción Forkhead/fisiología , Genes Supresores de Tumor , Enfermedad de Hodgkin/genética , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor/fisiología , Sitios Genéticos/genética , Enfermedad de Hodgkin/patología , Humanos , MicroARNs/genética , MicroARNs/fisiología , Proteína Oncogénica v-akt/genética , Proteína Oncogénica v-akt/metabolismo , Proteína Oncogénica v-akt/fisiología , Distribución TisularRESUMEN
Recently we have shown that the transcription factor FOXO1, highly expressed in B cells, is downregulated in classical Hodgkin lymphoma (cHL). As primary mediastinal B cell lymphoma (PMBL) has similarities with the cHL transcription program we investigated FOXO1 expression in this entity. By using immunohistochemistry we found that FOXO1 was absent or expressed at low levels in 19 of 20 primary PMBL cases. PMBL cell lines reproduce the low FOXO1 expression observed in primary cases. By analyzing gene expression profiling data we found that FOXO1 expression inversely correlated with JAK2 in PMBL cases. Targeting JAK2 activity by the small molecular weight inhibitor TG101348 resulted in upregulation of FOXO1 mRNA and protein expression in MedB-1 and U2940 cell lines, and the MYC inhibitor 10058-F4 increased FOXO1 mRNA in MedB-1 cells. Moreover, in MedB-1 cells FOXO1 expression was strongly upregulated by the inhibitor of DNA methylation 5-aza-2-deoxycytidine and by the histone deacetylase inhibitor trichostatin A. Since FOXO1 promoter was unmethylated, this effect is most likely indirect. FOXO1 activation in the FOXO1-negative Med-B1 cell line led to growth arrest and apoptosis, which was accompanied by repression of MYC and BCL2L1/BCLxL. Thus, FOXO1 repression might contribute to the oncogenic program and phenotype of PMBL.
Asunto(s)
Factores de Transcripción Forkhead/genética , Linfoma de Células B/genética , Neoplasias del Mediastino/genética , Apoptosis/genética , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Decitabina , Regulación hacia Abajo , Epigenómica , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/metabolismo , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Neoplasias del Mediastino/metabolismo , Neoplasias del Mediastino/patología , Transducción de SeñalRESUMEN
Liver regeneration requires spatially and temporally precisely coordinated proliferation of the two major hepatic cell populations, hepatocytes and liver sinusoidal endothelial cells (LSECs), to reconstitute liver structure and function. The underlying mechanisms of this complex molecular cross-talk remain elusive. Here, we show that the expression of Angiopoietin-2 (Ang2) in LSECs is dynamically regulated after partial hepatectomy. During the early inductive phase of liver regeneration, Ang2 down-regulation leads to reduced LSEC transforming growth factor-ß1 production, enabling hepatocyte proliferation by releasing an angiocrine proliferative brake. During the later angiogenic phase of liver regeneration, recovery of endothelial Ang2 expression enables regenerative angiogenesis by controlling LSEC vascular endothelial growth factor receptor 2 expression. The data establish LSECs as a dynamic rheostat of liver regeneration, spatiotemporally orchestrating hepatocyte and LSEC proliferation through angiocrine- and autocrine-acting Ang2, respectively.