Abstract
The connection between colorectal cancer (CRC) and Wnt signaling pathway activation is well known, but full elucidation of the underlying regulation of the Wnt/β-catenin pathway and its biological functions in CRC pathogenesis is still needed. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model has been used as an experimental platform able to mimic human sporadic CRC development with predictable timing. We performed genome-wide expression profiling of AOM/DSS-induced tumors and normal colon mucosa to identify potential novel CRC biomarkers. Remarkably, the enhanced expression of Notum, a conserved feedback antagonist of Wnt, was observed in tumors along with alterations in Glypican-1 and Glypican-3 levels. These findings were confirmed in a set of human CRC samples. Here, we provide the first demonstration of significant changes in Notum and glypicans gene expression during CRC development and present evidence to suggest them as potential new biomarkers of CRC pathogenesis.
Highlights
Colorectal cancer (CRC) is the third most common neoplastic disease worldwide and is the second leading cause of cancer death in the Western world [1]
The aim of our study was to identify novel genes that are deregulated in colorectal cancer using a reliable preclinical platform represented by the chemically induced mouse model of sporadic CRC
The most advanced adenomas and adenocarcinomas lack the strong www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget inflammatory background observed in other mouse models, which proceed through repeated cycles of DSS administration
Summary
Colorectal cancer (CRC) is the third most common neoplastic disease worldwide and is the second leading cause of cancer death in the Western world [1]. Wnt signaling pathway activation and mutations in the KRAS and APC genes in the majority of colorectal cancers have been demonstrated [2, 3]. Little is known regarding the fine regulation of the Wnt/β-catenin pathway or its biological functions that might be involved in the pathogenesis of CRC. Recent studies have focused on the activity of Wnt signals, showing that they are tightly controlled by various extracellular molecules. Kakugawa and colleagues recently added greatly to our understanding of Wnt signaling and the central role of Notum in the regulation of this pathway [4]. Hedgehog is another signaling molecule whose activity is modified by lipids, it has been demonstrated that, unlike Wnt, Hedgehog is not a substrate for Notum and that, in flies, Notum does not interact with Hedgehog signaling [4]. It has been shown that Notum contains binding sites for polysaccharides such as GPCs sugar chains, inviting speculation that GPCs bring together Notum and Wnt — modulating the enzymatic interaction of Notum with Wnt, rather than acting as a substrate for Notum to cleave GPI anchors [4]
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