Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma
Richard C. Bates, … , Peter Oettgen, Arthur M. Mercurio
Richard C. Bates, … , Peter Oettgen, Arthur M. Mercurio
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):339-347. https://doi.org/10.1172/JCI23183.
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Article Oncology

Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma

Abstract

We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the β6 integrin subunit and a consequent induction of αvβ6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-β and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of β6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of patients with high β6 expression. Elevated receptor expression did not simply reflect increasing tumor stage, since log-rank analysis showed a more significant impact on the survival of patients with early-stage, as opposed to late-stage, disease. Cox regression analysis confirmed that this integrin is an independent variable for these tumors. These findings define the αvβ6 integrin as an important risk factor for early-stage disease and a novel therapeutic candidate for colorectal cancer.

Authors

Richard C. Bates, David I. Bellovin, Courtney Brown, Elizabeth Maynard, Bingyan Wu, Hisaaki Kawakatsu, Dean Sheppard, Peter Oettgen, Arthur M. Mercurio

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Figure 2

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Transcriptional regulation of β6 by the Ets-1 transcription factor. (A) ...
Transcriptional regulation of β6 by the Ets-1 transcription factor. (A) Schematic of the human integrin β6 promoter. The transcription start site (TSS) and translation start site (ATG) are indicated. Putative Ets-binding sites are shown (triangles), and the 4 corresponding sequences are listed, including location detail. The consensus DNA-binding sequence (GGAA) is shown in bold. (B) Transactivation of the β6 luciferase reporter construct (–926/+208) by a panel of Ets transcription factors compared with the empty mammalian expression plasmid (PCI) in HEK293 cells. The change in luciferase activity is expressed as fold induction compared with PCI. (C) Gel mobility shift assay for Ets-1 binding to putative Ets sites in the β6 promoter. In vitro–translated Ets-1 protein or control extract was used with end-labeled oligonucleotide probes encoding putative Ets sites 1–4, as indicated. (D) Mutational analysis of the β6 promoter. Transactivation of either the wild-type (black bars) or mutant Ets-1–binding site –66/–63 (white bars) β6 luciferase reporter constructs in response to increasing doses of Ets-1 is shown.