期刊
ONCOGENE
卷 22, 期 40, 页码 6183-6193出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1206720
关键词
EGFR transactivation; GRPR; G-protein-coupled receptor; TGF-alpha; head and neck cancer
资金
- NCI NIH HHS [U01CA84968, P50CA90440, R01CA79882] Funding Source: Medline
Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor ( EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-alpha) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR- deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-alpha and require the activation of an EGFR- dependent MEK/MAPK-dependent pathway.
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