Epithelial to Mesenchymal Transition Is Impaired in Colon Cancer Cells With Microsatellite Instability

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

Research output: Contribution to journalArticle

75 Citations (Scopus)

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-β receptor type II (TGFBR2) gene. Methods: The induction of EMT by transforming growth factor-β1 (TGF-β1) 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-β1 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-β1. 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-β1, 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.

Original languageEnglish
Pages (from-to)1406-1417
Number of pages12
JournalGastroenterology
Volume138
Issue number4
DOIs
Publication statusPublished - Apr 2010

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Microsatellite Instability
Epithelial-Mesenchymal Transition
Colonic Neoplasms
Transforming Growth Factors
Colorectal Neoplasms
Reverse Transcription
Genotype
Phase-Contrast Microscopy
Polymerase Chain Reaction
Growth Factor Receptors
Extracellular Signal-Regulated MAP Kinases
Natural History
Immunoblotting
Microsatellite Repeats
Fluorescent Antibody Technique
Neoplasms
Immunohistochemistry
Phenotype
Gene Expression
DNA

Keywords

  • Colorectal Cancer
  • Epithelial to Mesenchymal Transition
  • Microsatellite Instability
  • Transforming Growth Factor-β Receptor Type II

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Pino, M. S., Kikuchi, H., Zeng, M., Herraiz, M. T., Sperduti, I., Berger, D., ... Chung, D. C. (2010). Epithelial to Mesenchymal Transition Is Impaired in Colon Cancer Cells With Microsatellite Instability. Gastroenterology, 138(4), 1406-1417. https://doi.org/10.1053/j.gastro.2009.12.010

Epithelial to Mesenchymal Transition Is Impaired in Colon Cancer Cells With Microsatellite Instability. / Pino, Maria S.; Kikuchi, Hirotoshi; Zeng, Min; Herraiz, Maria Teresa; Sperduti, Isabella; Berger, David; Park, Do Youn; Iafrate, A. John; Zukerberg, Lawrence R.; Chung, Daniel C.

In: Gastroenterology, Vol. 138, No. 4, 04.2010, p. 1406-1417.

Research output: Contribution to journalArticle

Pino, MS, Kikuchi, H, Zeng, M, Herraiz, MT, Sperduti, I, Berger, D, Park, DY, Iafrate, AJ, Zukerberg, LR & Chung, DC 2010, 'Epithelial to Mesenchymal Transition Is Impaired in Colon Cancer Cells With Microsatellite Instability', Gastroenterology, vol. 138, no. 4, pp. 1406-1417. https://doi.org/10.1053/j.gastro.2009.12.010
Pino, Maria S. ; Kikuchi, Hirotoshi ; Zeng, Min ; Herraiz, Maria Teresa ; Sperduti, Isabella ; Berger, David ; Park, Do Youn ; Iafrate, A. John ; Zukerberg, Lawrence R. ; Chung, Daniel C. / Epithelial to Mesenchymal Transition Is Impaired in Colon Cancer Cells With Microsatellite Instability. In: Gastroenterology. 2010 ; Vol. 138, No. 4. pp. 1406-1417.
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