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-β receptor type II (TGFBR2) gene. Methods The induction of EMT by TGF-β1 was analyzed by phase contrast microscopy, immunofluorescence, qRT-PCR, immunoblotting, and cellular migration and invasion assays. Expression of EMT markers was evaluated by immunohistochemistry and qRT-PCR 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 upon the recruitment of ERK. Tumor cells with MSI but wildtype 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.

The Iron Chelators Dp44mT and DFO Inhibit TGF-β-induced Epithelial-Mesenchymal Transition via Up-Regulation of N-Myc Downstream-regulated Gene 1 (NDRG1)

“…Consistent with the morphological changes, there was a significant (p Ͻ 0.001) 2-4-fold decrease in the expression of the epithelial markers, E-cadherin and ␤-catenin (7,32), and a significant (p Ͻ 0.001) 3-5-fold increase in the expression of the mesenchymal marker, vimentin (7,32), after TGF-␤ treatment of HT29 and DU145 cells (Fig. 2B).…”

“…Furthermore, for DU145 cells, incubation with TGF-␤ resulted in more spindle-shaped, fibroblast-like cells. These morphological characteristics were consistent with cells undergoing the EMT after incubation with TGF-␤ (32,33).…”

β-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness

“…Compared to sporadic CRCs, Lynch CRCs are less invasive and metastatic and have a more favorable prognosis. Over 90% of Lynch CRCs also present mutations of the TGFβ receptor type II compromising their ability to undergo an EMT in response to TGFβ, thus contributing to explain their lower invasiveness (28). Here, we have shown that, contrary to FAP tumors, Lynch CRCs with wild-type APC do not express ZEB1.…”

Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

“…PTBP1 silencing in colorectal cancer cells reduced the CD44 v8-10 ratio in HCT116 and DLD1, which are microsatellite-unstable cell lines that do not respond to TGFb-induced EMT (46). On the other hand, HT-29 and SW480 did not respond to siPTBP1 on splicing of CD44.…”