Notch signalling is off and is uncoupled from HES1 expression in Ewing's sarcoma

被引:24
作者
Bennani-Baiti, Idriss M. [1 ]
Aryee, Dave N. T. [1 ]
Ban, Jozef [1 ]
Machado, Isidro [2 ]
Kauer, Maximilian [1 ]
Muehlbacher, Karin [1 ]
Amann, Gabriele [3 ]
Llombart-Bosch, Antonio [2 ]
Kovar, Heinrich [1 ]
机构
[1] St Anna Kinderkrebsforschung, Childrens Canc Res Inst, A-1090 Vienna, Austria
[2] Univ Valencia, Dept Pathol, Sch Med, Valencia, Spain
[3] Univ Vienna, Inst Klin Pathol, Vienna, Austria
关键词
bHLH transcription factors; covariance meta-analysis; Ewing tumours; EWS-ETS; fusion oncogenes; medulloblastoma; Notch; paediatric cancers; rhabdomyosarcoma; tumour suppressors; ACUTE LYMPHOBLASTIC-LEUKEMIA; MESENCHYMAL TRANSITION; CELL-PROLIFERATION; TUMOR-SUPPRESSOR; STEM-CELLS; PATHWAY; DIFFERENTIATION; CANCER; ACTIVATION; INHIBITION;
D O I
10.1002/path.2966
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Notch can act as an oncogene or as a tumour suppressor and thus can either promote or inhibit tumour cell growth. To establish Notch status in Ewing's sarcoma family of tumours (ESFT), we investigated the Notch pathway by gene expression profiling meta-analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We found that although Notch receptors were highly expressed, Notch did not appear to be active, as evidenced by the absence of Notch receptors in cell nuclei. In contrast, we show that Notch receptors known to be active in colon adenocarcinoma, hepatocarcinoma, and pancreatic carcinoma stain cell nuclei in these tumours. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch, was also restricted to outside of the nucleus in the majority of ESFT, and analysis of HES1 gene targets indicated HES1 to be transcriptionally inactive. Neither forced activation nor pharmacological or genetic blocking of Notch affected HES1 expression in ESFT cells, indicating HES1 expression to be uncoupled from the Notch pathway. Additional functional studies in ESFT cell lines confirmed Notch to be switched off. Finally, unlike experiments in which HES1 expression was modulated, experimental activation of Notch in ESFT cell lines via several means blocked cell proliferation and reduced their clonogenic potential in soft agar. These indicate that HES1 is uncoupled from Notch in ESFT, that EWS-FLI1-mediated inhibition of Notch contributes to ESFT aggressive cell growth, and support a role for Notch in ESFT tumour suppression, at least partly through the Notch effector HEY1. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:353 / 363
页数:11
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