Dysregulated genes and miRNAs in the apoptosis pathway in colorectal cancer patients

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

doi:10.1007/s10495-018-1451-1

Martha L Slattery, Lila E Mullany + Show 4 more

Open Access

https://doi.org/10.1007/s10495-018-1451-1

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Journal: Apoptosis	Publication Date: Mar 7, 2018
Citations: 72	License type: open-access

Affiliation: University of Utah, Kaiser Permanente

Abstract

Apoptosis is genetically regulated and involves intrinsic and extrinsic pathways. We examined 133 genes within these pathways to identify whether they are expressed differently in colorectal carcinoma (CRC) and normal tissue (N = 217) and if they are associated with similar differential miRNA expression. Gene expression data (RNA-Seq) and miRNA expression data (Agilent Human miRNA Microarray V19.0) were generated. We focused on dysregulated genes with a fold change (FC) of > 1.50 or < 0.67, that were significant after adjustment for multiple comparisons. miRNA:mRNA seed-region matches were determined. Twenty-three genes were significantly downregulated (FC < 0.67) and 18 were significantly upregulated (FC > 1.50). Of these 41 genes, 11 were significantly associated with miRNA differential expression. BIRC5 had the greatest number of miRNA associations (14) and the most miRNAs with a seed-region match (10). Four of these matches, miR-145-5p, miR-150-5p, miR-195-5p, and miR-650, had a negative beta coefficient. CSF2RB was associated with ten total miRNAs (five with a seed-region match, and one miRNA, miR-92a-3p, with a negative beta coefficient). Of the three miRNAs associated with CTSS, miR-20b-5p, and miR-501-3p, had a seed-region match and a negative beta coefficient between miRNA:mRNA pairs. Several miRNAs that were associated with dysregulated gene expression, seed-region matches, and negative beta coefficients also were associated with CRC-specific survival. Our data suggest that miRNAs could influence several apoptosis-related genes. BIRC5, CTSS, and CSF2R all had seed-region matches with miRNAs that would favor apoptosis. Our study identifies several miRNA associated with apoptosis-related genes, that if validated, could be important therapeutic targets.

Highlights

Programmed cell death, or apoptosis, is genetically regulated [1]
We comprehensively evaluated all apoptosis genes identified in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to identify which genes are dysregulated in colorectal cancer (CRC)
Of the genes that were significantly differentially expressed in all CRC tumors combined, all but TUBA3E, were not downregulated in microsatellite stable (MSS) tumors with a fold change (FC) of < 0.67, and several genes

Summary

Introduction

Programmed cell death, or apoptosis, is genetically regulated [1]. Activation of CASP8 triggers the execution phase of apoptosis; CASP3 is thought to be the most important executioner caspase. The two main linked pathways in apoptosis are the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway. The intrinsic signaling pathway involves mechanisms whereby signals can have either a positive or negative affect on apoptosis. Negative signals from the lack of specific growth factors, hormones, or cytokines can result in loss of apoptotic suppression and the activation of apoptosis. These changes influence the mitochondrial membrane, activating the mitochondrial pathway.

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