RESUMO
Chronic lymphocytic leukemia (CLL) is a malignant disease of mature B lymphocytes. We have previously shown that a characteristic feature of CLL cells are high levels of expression and activity of protein kinase CbetaII (PKCbetaII), and that this might influence disease progression by modulating signaling in response to B-cell receptor engagement. The aim of the present work was to investigate the factors involved in stimulating PKCbetaII expression in CLL cells. Here we show that the activation of PKCbetaII in CLL cells stimulated with vascular endothelial growth factor (VEGF) can drive expression of the gene for PKCbeta, PRKCB1. We found that this effect of VEGF on PRKCB1 transcription is paralleled by high expression of PKCbetaII protein and therefore probably contributes to the malignant phenotype of CLL cells. Taken together, the data presented in this study demonstrate that VEGF, in addition to its role in providing prosurvival signals, also plays a role in overexpression of PKCbetaII, an enzyme with a specific pathophysiologic role in CLL.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Tirosina Quinase da Agamaglobulinemia , Sequência de Bases , Primers do DNA/genética , Ativação Enzimática/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Mesilatos/farmacologia , Regiões Promotoras Genéticas , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C beta , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Pirróis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de SinaisRESUMO
A key feature of chronic lymphocytic leukaemia (CLL) cells is overexpressed protein kinase CßII (PKCßII), an S/T kinase important in the pathogenesis of this and other B cell malignancies. The mechanisms contributing to enhanced transcription of the gene coding for PKCßII, PRKCB, in CLL cells remain poorly described, but could be important because of potential insight into how the phenotype of these cells is regulated. Here, we show that SP1 is the major driver of PKCßII expression in CLL cells where enhanced association of this transcription factor with the PRKCB promoter is likely because of the presence of histone marks permissive of gene activation. We also show how vascular endothelial growth factor (VEGF) regulates PRKCB promoter function in CLL cells, stimulating PKCß gene transcription via increased association of SP1 and decreased association of STAT3. Taken together, these results are the first to demonstrate a clear role for SP1 in the up regulation of PKCßII expression in CLL cells, and the first to link SP1 with the pathogenesis of this and potentially other B cell malignancies where PKCßII is overexpressed.
Assuntos
Leucemia Linfocítica Crônica de Células B/metabolismo , Proteína Quinase C beta/metabolismo , Fator de Transcrição Sp1/metabolismo , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/metabolismo , Linfócitos B/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Regiões Promotoras Genéticas , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Lung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an unmet public health need and the lung cancer research community worldwide is putting a lot of effort to utilise major lung cancer population programmes in order to develop such molecular tools. The study of cancer epigenetics in the last decade has radically altered our views in cancer pathogenesis, providing new insights in biomarker development for risk assessment, early detection and therapeutic stratification. DNA methylation and miRNAs have rapidly emerged as potential biomarkers in body fluids showing promise to assist the clinical management of lung cancer. These new developments are exemplified in this review, demonstrating the huge potential of clinical cancer epigenetics, but also critically discussing the necessary validation steps to bring epigenetic biomarkers towards clinical implementation and the weaknesses of current biomarker studies.