The expression of endothelin-1 in chronic lymphocytic leukemia is controlled by epigenetic mechanisms and extracellular stimuli.
Endothelin-1 (ET-1) is a hormone peptide widely expressed and is involved in several biological processes, important not only for normal cell function but also for tumor development, including cell proliferation, invasion, metastasis, angiogenesis and osteogenesis. In accordance, ET-1 was already shown to contribute to the growth and progression of many different solid cancers. We recently demonstrated that ET-1 has a role in the pathogenesis of chronic lymphocytic leukemia (CLL) where it is abnormally expressed. In the context of this malignancy, ET-1 is able to mediate survival, drug-resistance and growth signals in leukemic cells. Previous studies, not conducted in CLL, have shown that ET-1 regulatory mechanisms are numerous and cell specific. Here, we valued the expression of ET-1 in CLL, in relation to DNA methylation but also in response to stimulation of some important pathways for the dialogue between CLL and microenvironment. We found that a high methylation of ET-1 first intron affects the basal expression of ET-1 in CLL. Moreover, we showed that the activation of CD40 or Toll-like receptor (TLR) by extracellular stimuli produces an augment of ET-1 level in CLL cells. Finally, we demonstrated the fundamental role of NF-kB signalling pathway in promoting and maintaining ET-1 expression in CLL cells, both in basal conditions and after CD40 activation.
['Martinelli|Silvia|S|', 'Maffei|Rossana|R|', 'Fiorcari|Stefania|S|', 'Quadrelli|Chiara|C|', 'Zucchini|Patrizia|P|', 'Benatti|Stefania|S|', 'Potenza|Leonardo|L|', 'Luppi|Mario|M|', 'Marasca|Roberto|R|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D019013:CD40 Antigens D019175:DNA Methylation D019332:Endothelin-1 D044127:Epigenesis, Genetic D005260:Female D015870:Gene Expression D006801:Humans D015451:Leukemia, Lymphocytic, Chronic, B-Cell D008297:Male D008875:Middle Aged D016328:NF-kappa B D015398:Signal Transduction D051193:Toll-Like Receptors D014407:Tumor Cells, Cultured
Endothelin-1 Chronic lymphocytic leukemia DNA methylation NF-kB CD40 stimulation Transcriptional regulation