Abstract
Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase (MAPK). Here, we show that FGF receptor 1 (FGFR1), which is expressed mainly in neoplastic thyroid cells, propagates MAPK activation and promotes tumor progression. In contrast, FGFR2 is down-regulated in neoplastic thyroid cells through DNA promoter methylation. Reexpression of FGFR2 competes with FGFR1 for the immediate substrate FGFR substrate 2 to impede signaling upstream of the BRAF/MAPK pathway. These data unmask an epigenetically controlled FGFR2 signal that imposes precisely on the intragenically modified BRAF/MAPK pathway to modulate thyroid cancer behavior.
Highlights
Thyroid cancer is the most common endocrine malignancy and is increasing in incidence [1]
We previously reported that FGFR2 protein was undetectable in six human thyroid carcinoma cell lines
We show divergent expression and actions of FGF receptor 1 (FGFR1) and FGFR2 in thyroid carcinoma cells, disclosing cancerpromoting roles of FGFR1 and cancer-suppressive properties of FGFR2
Summary
Thyroid cancer is the most common endocrine malignancy and is increasing in incidence [1]. The majority of thyroid carcinomas are derived from follicular epithelial cells and show a spectrum of differentiation from indolent well-differentiated papillary and follicular carcinomas to the more aggressive poorly differentiated carcinoma and the rare but rapidly lethal undifferentiated carcinoma [2] This spectrum of progression has been linked with a pattern of cumulative genetic defects that correlates with tumor differentiation, aggressiveness, and metastatic potential [3]. Fibroblast growth factors (FGF) and FGF receptors (FGFR) are implicated in regulating endocrine neoplasia, including thyroid carcinoma [4, 5]. FGFs comprise a family of heparin-binding proteins that currently includes 23 members They signal through four highaffinity tyrosine kinase receptors No mutations or rearrangements involving FGFRs have been identified in thyroid cancers, suggesting that epigenetic factors are implicated in their dysregulated expression in thyroid tumors. I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-4477
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