Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells

Abstract

BackgroundNotch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL). Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α) activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL.MethodsT-ALL cell lines (Jurkat, Sup-T1) transfected with HIF-1α or Notch1 small interference RNA (siRNA) were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot.ResultsHypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2) and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression.ConclusionsNotch1 signalling is required for hypoxia/HIF-1α-induced proliferation, invasion and chemoresistance in T-ALL. Pharmacological inhibitors of HIF-1α or Notch1 signalling may be attractive interventions for T-ALL treatment.

Overexpression of HS6ST2 is associated with poor prognosis in patients with gastric cancer

“…The potential mechanism by which HS6ST2 potentiates PC carcinogenesis is mainly attributed to the activation of the notch-signaling pathway, which mediates EMT and angiogenesis (13). The notch-signaling pathway is involved in the processes of tumor cell proliferation, invasion, and the establishment of a mesenchymal phenotype (33,34). In thyroid carcinomas, HS6ST2 was identified as a target gene of twist family bhlh transcription factor 1, a critical regulator of EMT (10,35).…”

N6-methyladenosine is required for the hypoxic stabilization of specific mRNAs

“…This hallmark of the hypoxic response leads to increased translation of VEGF promoting vascular growth in order to increase the blood supply to affected cells, thereby leading to increased oxygen (Levy 1998;Levy et al 1998;Stein et al 1995;Arcondéguy et al 2013). The hypoxic response also aids tumor migration by up-regulating the genes that are involved in the degradation of the extracellular matrix, as well as increasing the metastatic ability of the tumor and cellular proliferation through genes such as dual specificity protein phosphatase 1 (Dusp1) and hairy and enhancer of split 1 (Hes1) (Wykoff et al 2001;Harris 2002;Giatromanolaki et al 2003;Rankin and Giaccia 2008;Zou et al 2013;Balamurugan 2015;Gao et al 2015;Shen et al 2016).…”

The TCR γδ Repertoire and Relative Gene Expression Characteristics of T-ALL Cases with Biclonal Malignant Vδ1 and Vδ2 T Cells

“…Notch1 signaling is crucial for T-cell differentiation and proliferation, and the mutational activation of Notch1 is an important factor in T-ALL pathogenesis (Koch and Radtke, 2011;Zou et al, 2013). Translocation and mutations in Notch1 may alter its function and result in overexpression and independent activation, and *60% of T-ALL cases show an increased Notch1 activity (Asnafi et al, 2009;Erbilgin et al, 2010;Koch and Radtke, 2011).…”

“…Moreover, complex acquired genetic aberrations, including chromosomal translocations, gene rearrangements, and mutations resulting in the abnormal expression of oncogenes may be associated with advanced disease and resistance to treatment. For example, CALM-AF10 has been associated with early relapse (Zheng et al, 2011a;Huang et al, 2012;Lin et al, 2012;Zou et al, 2013;Chen et al, 2013b), whereas the molecular mechanism of the poor prognosis of T-ALL is far from clear.…”