Membrane-tethered Notch1 exhibits oncogenic property via activation of EGFR-PI3K-AKT pathway in oral squamous cell carcinoma
| Autor: | Yi Zhong, Jialiang Li, Yunong Wu, Xianbin Xiong, Yibo Dong, Xiaomeng Song, Zaiou Zhu, Yang Zheng, Xiang Wang, Wei Zhang, Zhao Wang, Wenyi Gu, Heming Wu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Physiology Cellular differentiation Clinical Biochemistry 03 medical and health sciences Cell surface receptor Cell Movement hemic and lymphatic diseases Cell Line Tumor Humans Neoplasm Invasiveness Epidermal growth factor receptor Receptor Notch1 Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Oncogene Proteins biology Chemistry Cell growth Squamous Cell Carcinoma of Head and Neck Cell Biology ErbB Receptors 030104 developmental biology Notch proteins embryonic structures Mutation cardiovascular system Cancer research biology.protein Mouth Neoplasms sense organs biological phenomena cell phenomena and immunity Signal transduction Phosphatidylinositol 3-Kinase Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of cellular physiology. 234(5) |
| ISSN: | 1097-4652 |
| Popis: | Notch proteins are highly conserved cell surface receptors which play essential roles in cellular differentiation, proliferation, and apoptotic events at all stages of development. Recently, NOTCH1 mutations have been extensively observed in oral squamous cell carcinoma (OSCC) and are hinted to be Notch1-inactivating mutations. However, little is known about the biological effect of these reported mutations in OSCC. To mimic the inactivation of Notch1 due to inappropriate mutations and to determine the potential mechanisms, we utilized wild-type Notch1 vectors (Notch1WT ) or mutant Notch1 vectors (Notch1V1754L ) to transfect into OSCC cell lines. Membrane-tethered Notch1 induced by mutation was analyzed by immunofluorescence staining. γ-Secretase inhibitor PF-03084014 was utilized to determine the phenotype in the absence of endogenous Notch1 activation. Here we demonstrated that membrane-tethered Notch1 inactivated the canonical Notch1 signaling and oncogenic phenotypes were identified by promoting cell proliferation and invasion and by inducing epithelial-to-mesenchymal transition in cells. The γ-secretase inhibitor PF-03084014 also showed distinct oncogenic property after treatment. Importantly, both membrane-tethered Notch1 and PF-03084014 inhibitor activated the epidermal growth factor receptor (EGFR)-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which has been confirmed as an overwhelming modulator in OSCC. This was the first time that we clearly simulated the mutated Notch1 activities and determined the oncogenic phenotypes of membrane-tethered Notch1. Compared with wild-type Notch1, membrane-tethered Notch1 was strongly associated with activated EGFR-PI3K-AKT signaling pathway. |
| Databáze: | OpenAIRE |
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