The oncogenic roles of Notch1 in astrocytic gliomas in vitro and in vivo.
Notch receptors play an essential role in cellular processes during embryonic and postnatal development, including maintenance of stem cell self-renewal, proliferation, and determination of cell fate and apoptosis. Deregulation of Notch signaling has been implicated in some genetic diseases and tumorigenesis. The function of Notch signaling in a variety of tumors can be either oncogenic or tumor-suppressive, depending on the cellular context. In this study, Notch1 overexpression was observed in the majority of 45 astrocytic gliomas with different grades and in U251MG glioma cells. Transfection of siRNA targeting Notch1 into U251 cells in vitro downregulated Notch1 expression, associated with inhibition of cell growth, arrest of cell cycle, reduction of cell invasiveness, and induction of cell apoptosis. Meanwhile, tumor growth was delayed in established subcutaneous gliomas in nude mice treated with Notch1 siRNA in vivo. These results suggest that Notch1 plays an important oncogenic role in the development and progression of astrocytic gliomas. Furthermore, knockdown of Notch1 expression by siRNA simultaneously downregulated the expression of EGFR and the important components of its downstream pathways, including PI3K, p-AKT, K-Ras, cyclin D1 and MMP9, indicating the crosstalk and interaction of Notch and EGFR signaling pathways.
Xu
Peng
P
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
Qiu
Mingzhe
M
Zhang
Zhiyong
Z
Kang
Chunsheng
C
Jiang
Rongcai
R
Jia
Zhifan
Z
Wang
Guangxiu
G
Jiang
Hao
H
Pu
Peiyu
P
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001254:Astrocytoma / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection / Q000379:methods
D017304:Annexin A5; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D020780:Matrix Metalloproteinase 9; D016283:Proto-Oncogene Proteins p21(ras)