Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/β-catenin signaling is activated in human colon tumors

Abstract

Genetic studies have identified mutations in key regulators of the Wnt͞␤-catenin pathway in a variety of cancers, most frequently in colon cancers. However, whether the pathway is activated in clinical cancer samples is not easily determined, and therefore it is useful to find markers that could be surrogates to show activation of the Wnt͞␤-catenin pathway. Gene expression profiles were analyzed in SW620, a colon cancer cell line in which ␤-catenin levels are stabilized as a consequence of truncated adenomatous polyposis coli and were compared with profiles of the same cells transfected with antisense oligodeoxynucleotides. Treatment of cells with ␤-catenin antisense oligodeoxynucleotides resulted in a decrease in the levels of axin2 and human naked cuticle (hnkd) mRNAs. Interestingly, the proteins encoded by both of these mRNAs are known inhibitors of the ␤-catenin pathway. In 30 human cell lines derived from different origins, axin2 and hnkd were expressed only in human colon cancer cell lines that are known to have activating mutations in the Wnt͞␤-catenin pathway. Further, levels of both axin2 and hnkd mRNA were also found to be elevated in about 65% of laser microdissected cells from human colon tumors compared with laser microdissected cells of normal morphology from the same patient samples. The increased expression of axin2 and hnkd correlated with truncations in adenomatous polyposis coli in the same patient samples. These results reveal that it is possible to detect activation of a carcinogenic pathway in human cancer samples with specific markers.

Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16Ink4a loss

“…The transcription factor Sox10 provided the most dramatic example of differential marker gene expression, with robust expression in 6 of 10 DITs and undetectable expression in the remaining 4 ( Figure 1B). Thus, a majority of relapsed tumors appeared to have reactivated the Wnt pathway, and a subset of Wnt targets appeared to provide useful markers of pathway activation within neoplasia, as reported by others (22).…”

DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway

“…These include a number of genes important for development or tumorigenesis; for example, Myc, CyclinD1, Axin2, Siamois (Brannon et al, 1997;He et al, 1998;Shtutman et al, 1999;Tetsu and McCormick, 1999;Yan et al, 2001;Jho et al, 2002;Lustig et al, 2002). Most of these genes have one or more TCF-binding elements near the transcription start site in their promoter region.…”

CD44 functions in Wnt signaling by regulating LRP6 localization and activation

“…Prominent Wnt/β-catenin target genes include the protooncogene C-MYC, 4 the negative Wnt regulator AXIN2 5,6 and cluster of differentiation 44 (CD44). 7 CD44 transmembrane glycoproteins control growth, survival, differentiation and motility (reviewed in Naor et al 8 and Ponta et al 9 ).…”