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A critical role of c-Cbl-interacting protein of 85 kDa in the development and progression of head and neck squamous cell carcinomas through the ras-ERK pathway.
- Source :
-
Neoplasia (New York, N.Y.) [Neoplasia] 2010 Oct; Vol. 12 (10), pp. 789-96. - Publication Year :
- 2010
-
Abstract
- Activation of the transforming growth factor (TGF) α/epidermal growth factor receptor (EGFR)-mediated signaling pathway is a common mechanism for dysregulated growth of head and neck squamous cell carcinoma (HNSCC). c-Cbl-interacting protein of 85 kDa (CIN85) is an adaptor protein that facilitates EGFR internalization. Little is known, however, about a role of CIN85 in EGFR signaling as well as its relevance to tumor development and progression of HNSCC. Here, we demonstrate that CIN85 is highly expressed in HNSCC tumor samples compared with adjacent normal tissues, and this overexpression is significantly correlated with advanced clinical stage. The experiments using CIN85-overexpressing and knockdown HNSCC cell lines showed that CIN85 promotes HNSCC growth and facilitates EGFR internalization without apparently affecting phosphorylation of EGFR. Moreover, CIN85 promoted TGF-α-induced activation of Ras and phosphorylation of downstream molecules such as c-Raf, MEK, and extracellular signal-regulated kinase, leading to expression of c-Myc that is critical for sustained proliferation of HNSCC. Taken together, these findings suggest that CIN85 not only controls EGFR internalization but also promotes the EGFR-mediated tumor development and progression, and thus, CIN85 may serve as a potential therapeutic target in a subset of HNSCC.
- Subjects :
- Apoptosis
Blotting, Western
Carcinoma, Squamous Cell secondary
Cell Proliferation
Disease Progression
ErbB Receptors genetics
ErbB Receptors metabolism
Female
Head and Neck Neoplasms pathology
Humans
Immunoenzyme Techniques
Lymphatic Metastasis
MAP Kinase Kinase 1 genetics
MAP Kinase Kinase 1 metabolism
Male
Microscopy, Fluorescence
Middle Aged
Mitogen-Activated Protein Kinase 1 genetics
Mitogen-Activated Protein Kinase 3 genetics
Phosphorylation
Proto-Oncogene Proteins c-raf genetics
RNA, Messenger genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Transforming Growth Factor alpha pharmacology
Tumor Cells, Cultured
Adaptor Proteins, Signal Transducing physiology
Carcinoma, Squamous Cell metabolism
Head and Neck Neoplasms metabolism
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Proto-Oncogene Proteins c-raf metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5586
- Volume :
- 12
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Neoplasia (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 20927317
- Full Text :
- https://doi.org/10.1593/neo.10396