The aberrant methylation of TSP1 suppresses TGF-ß1 activation in colorectal cancer
Por:
Rojas A., Meherem S., Kim Y.-H., Washington M.K., Willis J.E., Markowitz S.D., Grady W.M.
Publicada:
1 ene 2008
Resumen:
Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-ß pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-ß ligand activation, is an epigenetic mechanism for inhibiting the TGF-ß signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-ß signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-ß1 and attenuated TGF-ß signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-ß complex and subsequent TGF-ß receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-ß signaling in colorectal cancer. © 2008 Wiley-Liss, Inc.
Filiaciones:
Rojas A.:
Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN, United States
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Meherem S.:
Department of Medicine, Vanderbilt University Medical School, Nashville, TN, United States
Kim Y.-H.:
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Washington M.K.:
Department of Pathology, Vanderbilt University Medical School, Nashville, TN, United States
Willis J.E.:
Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
Markowitz S.D.:
Howard Hughes Medical Institute, Cleveland, OH, United States
Grady W.M.:
Department of Cancer Biology, Vanderbilt University Medical School, Nashville, TN, United States
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Department of Medicine, University of Washington Medical School, Seattle, WA, United States
R and D Service, VA Puget Sound Health Care System, Seattle, WA, United States
Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N. D4-100, Seattle, WA 98109, United States
|