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Epigenetically controlled fibroblast growth factor receptor 2 signaling imposes on the RAS/BRAF/mitogen-activated

Tetsuo Kondo1, Lei Zheng, Wei Liu

  • 1Department of Pathology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.

Cancer Research
|June 5, 2007
PubMed

Insights

Fibroblast growth factor (FGF) signaling impacts thyroid cancer. FGF receptor 1 (FGFR1) promotes tumor growth, while FGFR2, epigenetically silenced, can impede it by modulating the BRAF/MAPK pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Fibroblast growth factor (FGF) signaling is crucial in both normal development and cancer progression.
  • Thyroid cancer often exhibits genetic mutations that activate the mitogen-activated protein kinase (MAPK) pathway.
  • Understanding the roles of specific FGF receptors in thyroid tumorigenesis is essential.

Purpose of the Study:

  • To investigate the distinct roles of FGF receptor 1 (FGFR1) and FGF receptor 2 (FGFR2) in thyroid cancer progression.
  • To elucidate the mechanisms by which FGFR2 expression is regulated and its impact on MAPK signaling.
  • To uncover the interplay between epigenetic modifications and intragenic mutations in thyroid cancer.

Main Methods:

  • Analysis of FGFR1 and FGFR2 expression in neoplastic thyroid cells.
  • Investigation of DNA promoter methylation as a mechanism for FGFR2 regulation.
  • Functional studies assessing the impact of FGFR2 re-expression on MAPK pathway activation and tumor progression.
  • Examination of the interaction between FGFRs and FGFR substrate 2 (FGF RS2) in the context of the BRAF/MAPK pathway.

Main Results:

  • FGFR1 is predominantly expressed in neoplastic thyroid cells, propagating MAPK activation and promoting tumor progression.
  • FGFR2 is epigenetically silenced in neoplastic thyroid cells via DNA promoter methylation.
  • Re-expression of FGFR2 competes with FGFR1 for FGF RS2, thereby inhibiting signaling upstream of the BRAF/MAPK pathway.
  • These findings reveal an epigenetically regulated FGFR2-mediated signal that influences the BRAF/MAPK pathway in thyroid cancer.

Conclusions:

  • Epigenetic silencing of FGFR2 plays a significant role in thyroid cancer progression.
  • FGFR2 acts as a tumor suppressor by antagonizing FGFR1-driven MAPK activation.
  • Targeting epigenetic mechanisms to restore FGFR2 function may offer a therapeutic strategy for thyroid cancer.

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