Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells.
Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells.
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Notch1是缺氧诱导T细胞急性淋巴细胞白血病细胞增殖、侵袭和化疗耐药所必需的
DOI：
10.1186/1756-8722-6-3
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发表时间：
2013-01-05
影响因子：
28.5
通讯作者：
Ji C
中科院分区：
文献类型：
--
作者：
Zou J;Li P;Lu F;Liu N;Dai J;Ye J;Qu X;Sun X;Ma D;Park J;Ji C
Notch 1是一种有效的调节因子，已知在包括T细胞急性淋巴细胞白血病（T-ALL）在内的许多恶性肿瘤中发挥致癌作用。肿瘤缺氧和缺氧诱导因子-1 α（HIF-1α）活性增加可作为肿瘤侵袭性和进展的主要刺激。尽管缺氧介导的Notch 1通路激活在肿瘤细胞存活和侵袭中起重要作用，但HIF-1α和Notch 1之间的相互作用尚未在T-ALL中确定。本研究旨在探讨缺氧是否通过HIF-1α稳定化激活Notch 1信号传导，并确定缺氧和HIF-1α对T-ALL增殖、侵袭和化疗耐药性的贡献。将转染HIF-1α或Notch 1小干扰RNA（siRNA）的T-ALL细胞系（Jurkat、Sup-T1）在常氧或低氧条件下孵育。通过WST-8和transwell测定来测量它们的增殖和侵袭潜力。流式细胞术检测细胞凋亡和细胞周期调控。通过实时定量PCR或Western blot评估HIF-1α和Notch 1通路的组分以及与增殖、侵袭和凋亡相关的基因的表达和调节。缺氧通过稳定和激活转录因子HIF-1α增强Notch 1信号传导。缺氧/HIF-1α激活的Notch 1信号改变了细胞周期调控蛋白的表达，加速了细胞增殖。缺氧诱导的Notch 1活化增加基质金属蛋白酶2（MMP 2）和MMP 9的表达，从而增加侵袭性。Notch 1的敲低可阻止缺氧/HIF-1α对地塞米松诱导的细胞凋亡的保护作用，这具有更大的临床意义。这种致敏作用与缺氧/HIF-1α对Bcl-2和Bcl-xL表达的影响消失有关。Notch 1信号是T-ALL中缺氧/HIF-1α诱导的增殖、侵袭和化疗耐药所必需的。HIF-1α或Notch 1信号传导的药理学抑制剂可能是T-ALL治疗的有吸引力的干预措施。
Notch1 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. T-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. Hypoxia 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. Notch1 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.
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缺氧会增强乳腺癌中的 Notch 信号传导，导致 E-钙粘蛋白表达减少，细胞迁移和侵袭增加。
影响因子：
8.8
作者：
Chen, J.;Imanaka, N.;Chen, J.;Griffin, J. D.
通讯作者：
Griffin, J. D.
DOI：
10.1073/pnas.93.18.9493
发表时间：
1996-09-03
影响因子：
11.1
作者：
Hochachka, PW;Buck, LT;Land, SC
通讯作者：
Land, SC
低氧诱导因子-1α和Notch信号传导的相互作用调节髓母细胞瘤的前体增殖和命运。
影响因子：
5.2
作者：
Pistollato, Francesca;Rampazzo, Elena;Persano, Luca;Abbadi, Sara;Frasson, Chiara;Denaro, Luca;D'Avella, Domenico;Panchision, David M.;Della Puppa, Alessandro;Scienza, Renato;Basso, Giuseppe
通讯作者：
Basso, Giuseppe
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
20.3
作者：
Nefedova, Yulia;Sullivan, Daniel M.;Gabrilovich, Dmitry I.
通讯作者：
Gabrilovich, Dmitry I.