Genetic variants in the TGFβ-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue.

Martha L Slattery,Jennifer S Herrick,Andrew J Pellatt,Roger K Wolff,Andromahi Trivellas,Lila E Mullany,John R Stevens

doi:10.18632/oncotarget.14508

Martha L Slattery, Jennifer S Herrick + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.14508

Copy DOI

Abstract

The TGF-β signaling pathway is involved in regulation of cell growth, angiogenesis, and metastasis. We test the hypothesis that genetic variation in the TGF-β signaling pathway alters miRNA expression.We use data from 1188 colorectal cancer cases to evaluate associations between 80 SNPs in 21 genes.Seven variants eIF4E rs12498533, NFκB1 rs230510, TGFB1 rs4803455, TGFBR1 rs1571590 and rs6478974, SMAD3 rs3743343, and RUNX1 rs8134179 were associated with expression level of miRNAs in normal colorectal mucosa. RUNX2 rs12333172 and BMPR1B rs13134042 were associated with miRNAs in normal colon mucosa; eIF4EBP3 rs250425, SMAD3 rs12904944, SMAD7 rs3736242, and PTEN rs532678 were associated with miRNA expression in normal rectal mucosa. Evaluation of the differential expression between carcinoma and normal mucosa showed that SMAD3 rs12708491 and rs2414937, NFκB1 rs230510 and rs3821958, and RUNX3 rs6672420 were associated with several miRNAs for colorectal carcinoma. Evaluation of site-specific differential miRNA expression showed that BMPR1B rs2120834, BMPR2 rs2228545, and eIF4EBP3 rs250425 were associated with differential miRNA expression in colon tissue and SMAD3 rs12901071, rs1498506, and rs2414937, BMPR2 rs2228545, and RUNX2 rs2819854, altered differential miRNA expression in rectal tissue.These data support the importance of the TGF-β signaling pathway to the carcinogenic process, possibly through their influence on miRNA expression levels.

Highlights

The TGF-β signaling pathway is an essential regulator of cellular proliferation, differentiation, apoptosis, extracellular matrix remodeling in the cell, and is involved in angiogenesis and inflammation [1, 2]
MiRNA expression level differed across genotypes of seven SNPs, Eukaryotic translation initiation factor 4E (eIF4E) rs12498533, NFκB1 rs230510, TGFB1 rs4803455, TGFBR1 rs1571590 and rs6478974, SMAD3 rs3743343, and RUNX1 rs8134179 in normal colorectal mucosa (Table 2)
For EIF4E rs12498533, NFKB1 rs230510, SMAD3 rs3743343, TGFB1 rs4803455, all miRNAs were downregulated in the presence of the variant allele

Summary

Introduction

The TGF-β signaling pathway is an essential regulator of cellular proliferation, differentiation, apoptosis, extracellular matrix remodeling in the cell, and is involved in angiogenesis and inflammation [1, 2]. Components of this pathway have been associated with colorectal cancer risk and survival [3,4,5,6,7,8]. The Runtrelated transcription factors (RUNX), RUNX1, RUNX2, and RUNX3 [12] are involved in signaling cascades mediated by TGF-β and BMP [13,14,15,16]. Eukaryotic translation initiation factor 4E (eIF4E) is a translational regulator; expression of eIF4E in human colon cancer cells promotes the TGFβ www.impactjournals.com/oncotarget

Methods

Results

Conclusion