Expression of Wnt-signaling pathway genes and their associations with miRNAs in colorectal cancer.

Martha L Slattery,John R Stevens,Jennifer S Herrick,Lori C Sakoda,Roger K Wolff,Lila E Mullany,Wade S Samowitz

doi:10.18632/oncotarget.23636

Martha L Slattery, John R Stevens + Show 5 more

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https://doi.org/10.18632/oncotarget.23636

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Abstract

The Wnt-signaling pathway functions in regulating cell growth and thus is involved in the carcinogenic process of several cancers, including colorectal cancer. We tested the hypothesis that multiple genes in this signaling pathway are dysregulated and that miRNAs are associated with these dysregulated genes. We used data from 217 colorectal cancer (CRC) cases to evaluate differences in Wnt-signaling pathway gene expression between paired CRC and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most strongly associated with CRC (fold change (FC) of >1.5 or <0.67) and that were statistically significant after adjustment for multiple comparisons. Of the 138 Wnt-signaling pathway genes examined, 27 were significantly down-regulated (FC<0.67) and 32 genes were significantly up-regulated (FC>1.50) after adjusting for multiple comparisons. Thirteen of the 66 Wnt-signaling genes that were differentially expressed in CRC tumors were associated with differential expression of miRNAs. A total of 93 miRNA:mRNA associations were detected for these 13 genes. Of these 93 associations, 36 miRNA seed-region matches were observed, suggesting that miRNAs have both direct and indirect effects on Wnt-signaling pathway genes. In summary, our data supports the hypothesis that the Wnt-signaling pathway is dysregulated in CRC and suggest that miRNAs may importantly influence that dysregulation.

Highlights

The Wnt-signaling pathway is an important signaling pathway in many types of cancer including colorectal cancer (CRC) [1]
We focused on genes most strongly associated with CRC (fold change (FC) of >1.5 or
Of the 138 Wnt-signaling pathway genes examined (43.5%), 27 were significantly down-regulated (FC1.50) after adjusting for multiple comparisons when evaluating CRC tumors overall (Supplementary Table 1), this compares to 37.5% of all protein-coding genes being dysregulated (6541 dysregulated of 17461 protein-coding genes)

Summary

Introduction

The Wnt-signaling pathway is an important signaling pathway in many types of cancer including colorectal cancer (CRC) [1]. The canonical Wnt-signaling pathway, and the one studied the most with CRC, is mediated via Wnt ligands and their receptors resulting in accumulation of β-catenin [2] Components of this pathway include the adenomatous polyposis coli (APC). Gene which is mutated in roughly 80% of CRC, AXIN 1 and 2, and glycogen synthase kinase 3β (GSK-3β) [3] Downstream genes in this pathway include c-myc, c-jun, and Cyclin D1 (CCND1). Two non-canonical Wnt-signaling pathways, Wnt/CA2+ and Wnt/planar cell polarity (PCP), exist [4] While these Wnt-signaling pathways have been studied less thoroughly than the canonical Wnt/β-catenin pathway, it is felt that the Wntsignaling pathways do not operate independently of each www.impactjournals.com/oncotarget other. For instance both CaMKII and NFAT in the Wnt/ CA2+ pathway influence β-catenin [5]; β-catenin has been linked to JNK in the Wnt/PCP pathway [6]; and drug response may be influenced by both the canonical and non-canonical pathways [7]

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