Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion.
Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion.
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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。
DOI：
10.1038/sj.bjc.6605486
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发表时间：
2010-01-19
影响因子：
8.8
通讯作者：
Griffin, J. D.
中科院分区：
文献类型：
--
作者：
Chen, J.;Imanaka, N.;Chen, J.;Griffin, J. D.
关键词：
上皮-间质转化（EMT）与乳腺癌细胞的粘附力降低和转移潜能的获得有关。上皮向间充质转化部分由两种转录抑制因子Snail和Slug介导，这两种转录抑制因子已知是Notch信号通路的靶点，并且JAGGED 1诱导的Notch活化增加EMT。然而，导致乳腺癌细胞EMT期间Notch活性增加的事件尚不清楚。通过Western blot分析检测缺氧诱导因子（HIF）在缺氧条件下的积累，并通过体外Notch报告基因分析检测HIF对Notch信号转导的影响。实时荧光定量PCR检测缺氧条件下Notch靶基因的表达。HIF-1α基因的下调是通过逆转录病毒介导的。实时荧光定量PCR检测Slug和Snail在缺氧条件下的表达。用细胞迁移和侵袭试剂盒检测乳腺癌细胞在缺氧条件下的迁移和侵袭能力。缺氧增加了Notch靶基因如HES 1和HEY 1在乳腺癌细胞中的表达，Notch受体和配体的表达也是如此。其机制可能涉及缺氧引起的HIF-1α和HIF-2α在这些细胞中的积累，其与Notch共激活因子MAML 1协同增强Notch活性。低氧诱导因子-1 α在低氧条件下可与HES 1启动子结合。用shRNA敲低HIF-1α可抑制缺氧条件下HES 1和HEY 1的表达。缺氧可增加Slug和Snail的表达，减少E-cadherin的表达，这是EMT的标志。Notch通路抑制消除了低氧介导的Slug和Snail表达增加，以及降低了乳腺癌细胞的迁移和侵袭。缺氧介导的Notch信号可能在EMT的启动和随后的乳腺癌转移中起重要作用。
Epithelial-to-mesenchymal transition (EMT) is associated with decreased adhesion and acquisition of metastatic potential of breast cancer cells. Epithelial-to-mesenchymal transition is mediated, in part, by two transcription repressors, Snail and Slug, that are known to be targets of the Notch signaling pathway, and JAGGED1-induced Notch activation increases EMT. However, the events that lead to increased Notch activity during EMT of breast cancer cells are unknown. The accumulation of hypoxia inducible factors (HIFs) under hypoxia was detected by western blot analysis, and their effects on Notch signaling were measured by an in vitro Notch reporter assay. The expression of Notch target genes under hypoxia was tested by real-time PCR. The knockdown of HIF-1α was mediated by retroviral delivery of shRNA. The expression of Slug and Snail under hypoxia was measured by real-time PCR. Breast cancer cell migration and invasion under hypoxia were tested with cell migration and invasion kits. Hypoxia increased the expression of Notch target genes such as HES1 and HEY1 in breast cancer cells, as was expression of Notch receptors and ligands. The mechanism is likely to involve the accumulation of HIF-1α and HIF-2α in these cells by hypoxia, which synergised with the Notch co-activator MAML1 in potentiating Notch activity. Hypoxia inducible factor-1α was found to bind to HES1 promoter under hypoxia. Knockdown of HIF-1α with shRNA inhibited both HES1 and HEY1 expression under hypoxia. Hypoxia increased the expression of Slug and Snail, and decreased the expression of E-cadherin, hallmarks of EMT. Notch pathway inhibition abrogated the hypoxia-mediated increase in Slug and Snail expression, as well as decreased breast cancer cell migration and invasion. Hypoxia-mediated Notch signaling may have an important role in the initiation of EMT and subsequent potential for breast cancer metastasis.
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DOI：
10.1073/pnas.0603371103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Klinakis, Apostolos;Szaboics, Matthias;Efstratiadis, Argiris
通讯作者：
Efstratiadis, Argiris
影响因子：
50.3
作者：
Moody, SE;Perez, D;Chodosh, LA
通讯作者：
Chodosh, LA
影响因子：
15.9
作者：
Bedogni, Barbara;Warneke, James A.;Powell, Marianne Broome
通讯作者：
Powell, Marianne Broome
影响因子：
8
作者：
Diévart, A;Beaulieu, N;Jolicoeur, P
通讯作者：
Jolicoeur, P
影响因子：
8
作者：
Gallahan, D;Callahan, R
通讯作者：
Callahan, R