Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability.

Abstract

BACKGROUND & AIMS:

Colorectal cancers (CRCs) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial to mesenchymal transition (EMT) is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor-beta receptor type II (TGFBR2) gene.

METHODS:

The induction of EMT by transforming growth factor-beta1 (TGF-beta1) was analyzed by phase contrast microscopy, immunofluorescence, quantitative reverse transcription polymerase chain reaction, immunoblotting, and cellular migration, and invasion assays. Expression of EMT markers was evaluated by immunohistochemistry and quantitative reverse transcription polymerase chain reaction in a series of human colorectal tumors.

RESULTS:

TGF-beta1 induced changes in cellular morphology, gene expression, motility, and invasion consistent with EMT in microsatellite stable (MSS) colon cancer cells, whereas cells with MSI and mutant TGFBR2 were unresponsive to TGF-beta1. These effects did not require Smad4, but depended on the recruitment of extracellular signal-regulated kinase. Tumor cells with MSI but wild-type TGFBR2 underwent EMT in response to TGF-beta1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of EMT markers was significantly associated with adverse clinicopathologic features and the absence of MSI.

CONCLUSIONS:

These findings define a unique genotype-phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI.

• Authors: Maria S Pino, Hirotoshi Kikuchi, Min Zeng, Maria-Teresa Herraiz, Isabella Sperduti, David Berger, Do-Youn Park, A John Iafrate, Lawrence R Zukerberg, Daniel C Chung
• Journal: Gastroenterology (Gastroenterology) Vol. 138 Issue 4 Pg. 1406-17 (Apr 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 20026115 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cadherins
• Receptors, Transforming Growth Factor beta
• SMAD2 protein, human
• Smad2 Protein
• Transforming Growth Factor beta1
• Protein Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Active Transport, Cell Nucleus
• Adult
• Aged
• Cadherins (analysis)
• Cell Dedifferentiation (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Colonic Neoplasms (genetics, pathology)
• Epithelial Cells (pathology)
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Female
• Humans
• Male
• Mesoderm (pathology)
• Microsatellite Instability
• Middle Aged
• Neoplasm Invasiveness
• Protein Serine-Threonine Kinases (genetics)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (genetics)
• Smad2 Protein (metabolism)
• Transforming Growth Factor beta1 (pharmacology)