Death receptor 5 (DR5) and a 5-gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer.

Marina Devetzi,Theodosia Choreftaki,Margarita Vlassi,Iraklis Perysinakis,Chrysanthi Aggeli,Georgios N Zografos,Vivian Kosmidou,Alexander Pintzas

doi:10.1038/srep36532

Marina Devetzi, Theodosia Choreftaki + Show 6 more

Open Access

https://doi.org/10.1038/srep36532

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Abstract

High expression of Inhibitor of apoptosis proteins (IAPs) has been related to colorectal cancer (CRC) progression, resistance to treatment and poor prognosis. TRAIL (TNF-related apoptosis-inducing ligand) through its receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) can selectively induce cancer cell apoptosis. The mRNA expression of DR4, DR5, c-IAP1, c-IAP2, XIAP and BIRC5/Survivin genes was examined in 100 paired (cancerous-normal) colorectal tissue specimens by real-time PCR, 50 of which were KRAS wild-type and 50 KRAS-mutant. DR5, XIAP and BIRC5/Survivin genes are significantly up-regulated (p < 0.0001, p = 0.012 and p = 0.0003, respectively), whereas c-IAP1 and c-IAP2 genes are significantly down-regulated at mRNA and protein levels in CRC (p < 0.0001 for both). ROC analyses showed that DR5, cIAP1 and cIAP2 expression has discriminatory value between CRC and normal tissue (AUC = 0.700, p < 0.0001 for DR5; AUC = 0.628, p = 0.011 for cIAP1; AUC = 0.673, p < 0.0001 for cIAP2). Combinatorial ROC analysis revealed the marginally fair discriminatory value of 5 genes as a panel (AUC = 0.685, p < 0.0001). Kaplan-Meier survival curves revealed significant association of cIAP2 down-regulation in CRC with lower overall survival probability of CRC patients (p = 0.0098). DR5, BIRC5/Survivin, XIAP, c-IAP1 and c-IAP2 mRNA expression are significantly deregulated in CRC and could provide a panel of markers with significant discriminatory value between CRC and normal colorectal tissue.

Highlights

Colorectal cancer (CRC) is one of the most frequently diagnosed types of cancer in western industrialized countries[1]
Bavi et al reported that DR4 was significantly up-regulated in colorectal cancer (CRC) and adenomas by immunohistochemistry and was associated with a less aggressive phenotype characterized by early stage disease, whereas DR5 was associated with a microsatellite stable (MS–S/L) phenotype and with absence of KRAS mutations in a Middle-Eastern population[24]
In the current study we examined 100 cancerous and 100 normal paired colorectal tissues for the mRNA expression levels of DR5, DR4 and BIRC5/Survivin, XIAP, cIAP1, cIAP2 (IAPs) genes, using quantitative real-time PCR analysis

Summary

Introduction

Colorectal cancer (CRC) is one of the most frequently diagnosed types of cancer in western industrialized countries[1]. One of the most frequently mutated genes in CRC is the KRAS oncogene, component of the RAS/RAF/MEK/ERK signaling pathway downstream of EGFR (Epidermal Growth Factor Receptor), which is a significant regulator of cell growth, proliferation, differentiation and apoptosis. Imbalance in cell death signaling is implicated in CRC, since it is well known that the failure of apoptotic cell death pathways constitutes a crucial process for the survival of cancer cells and a leading cause of resistance to current therapeutic approaches[12,13]. Bavi et al reported that DR4 was significantly up-regulated in CRC and adenomas by immunohistochemistry and was associated with a less aggressive phenotype characterized by early stage disease, whereas DR5 was associated with a microsatellite stable (MS–S/L) phenotype and with absence of KRAS mutations in a Middle-Eastern population[24]. IAPs act as modulators of cell viability by inducing pro-survival signaling pathways

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