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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cell Growth Processes / physiology
-
Cell Line, Tumor
-
DNA Methylation
-
Disease Progression
-
Down-Regulation
-
Epigenesis, Genetic
-
Humans
-
MAP Kinase Signaling System / genetics
-
Neoplasm Invasiveness
-
Proto-Oncogene Proteins B-raf / genetics
-
Proto-Oncogene Proteins B-raf / metabolism*
-
RNA, Small Interfering / genetics
-
Receptor, Fibroblast Growth Factor, Type 1 / biosynthesis
-
Receptor, Fibroblast Growth Factor, Type 1 / genetics
-
Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
-
Receptor, Fibroblast Growth Factor, Type 2 / biosynthesis
-
Receptor, Fibroblast Growth Factor, Type 2 / genetics
-
Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
-
Thyroid Neoplasms / enzymology
-
Thyroid Neoplasms / genetics
-
Thyroid Neoplasms / metabolism*
-
Thyroid Neoplasms / pathology
-
Transfection
-
ras Proteins / genetics
-
ras Proteins / metabolism*
Substances
-
RNA, Small Interfering
-
FGFR1 protein, human
-
FGFR2 protein, human
-
Receptor, Fibroblast Growth Factor, Type 1
-
Receptor, Fibroblast Growth Factor, Type 2
-
BRAF protein, human
-
Proto-Oncogene Proteins B-raf
-
ras Proteins