Regulation of cell-cell contact molecules and the metastatic phenotype of medullary thyroid carcinoma by the Raf-1/MEK/ERK pathway

Surgery. 2008 Dec;144(6):920-4; discussion 924-5. doi: 10.1016/j.surg.2008.07.020.


Background: Medullary thyroid carcinoma (MTC) is highly metastatic. We have recently reported that activation of the Raf-1/MEK/ERK signaling pathway in MTC cells results in morphologic changes. We hypothesized that Raf-1-induced morphologic changes could be associated with alterations in cell-cell contact molecules, thereby affecting the metastatic potential of MTC cells.

Methods: An estradiol (E(2))-inducible Raf-1 MTC cell line (TT-raf) was utilized in this study. Western blot analysis was used to confirm the Raf-1/MEK/ERK pathway activation and to measure levels of essential cell-cell contact molecules. Assays for cell adhesion and migration were performed to investigate the cell motility.

Results: E(2) treatment of TT-raf cells resulted in the Raf-1/MEK/ERK pathway activation as evidenced by increased levels of phospho-MEK1/2 and -ERK1/2. This resulted in significant reductions in levels of essential cell-cell contact molecules including E-cadherin, beta-catenin, and occludin. Importantly, activation of the Raf-1/ MEK/ERK pathway and the associated decrease in essential cell-cell contact molecules dramatically inhibited the abilities of adhesion and migration in MTC cells. Furthermore, treatment of Raf-1-activated cells with U0126, a specific inhibitor of MEK, abrogated these Raf-1-induced effects indicating that the suppression of the metastatic phenotype in MTC cells is a MEK-dependent pathway.

Conclusion: These data suggest that the Raf-1/MEK/ERK pathway regulates essential cell-cell contact molecules and metastatic phenotype of MTC cells. Thus, these findings provide further insight into the key steps in the metastatic progression of MTC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Medullary / metabolism
  • Carcinoma, Medullary / physiopathology*
  • Cell Adhesion
  • Cell Adhesion Molecules / biosynthesis*
  • Cell Line, Tumor
  • Cell Movement
  • Humans
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Signal Transduction
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / physiopathology*
  • raf Kinases / metabolism*


  • Cell Adhesion Molecules
  • raf Kinases
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases