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Death Receptor 5 (DR5) and a 5-gene Apoptotic Biomarker Panel With Significant Differential Diagnostic Potential in Colorectal Cancer

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Death Receptor 5 (DR5) and a 5-gene Apoptotic Biomarker Panel With Significant Differential Diagnostic Potential in Colorectal Cancer

Marina Devetzi et al. Sci Rep.

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.

Figures

Figure 1
Figure 1
(A) Box plots show the significantly increased mRNA expression of DR5 in TNM stage classified CRC tissues. Quartiles (25th, 50th-median, 75th percentiles) are within the box. The horizontal lines indicate the medians. The upper and nether horizontal lines indicate the 90th and 10th percentiles, respectively, (B) Box plots show the significantly increased mRNA expression of DR5 in lymph node invasion status classified CRC tissues, (C) Box plots show the significantly decreased mRNA expression of cIAP1 in TNM stage-classified CRC tissues. (D) Box plots show the significantly decreased mRNA expression of cIAP1 in lymph node invasion status-classified CRC tissues.
Figure 2
Figure 2
ROC curve analyses indicating the discriminatory potential of DR5 (A), DR4 (C), BIRC5/Survivin (E), XIAP (G), cIAP1 (I) and cIAP2 (K) mRNA expression levels in CRC and normal tissues. Kaplan-Meier curves for OS of CRC patients with DR5-high and DR5-low (B), DR4-high and DR4-low (D), BIRC5-high and BIRC5-low (F), XIAP-high and XIAP-low (H), cIAP1-high and cIAP1-low (J) and cIAP2-high and cIAP2-low (L) gene expression.
Figure 3
Figure 3. A 5-gene ROC curve analysis for the discrimination between CRC and normal tissues.
Quantitative 5-gene PCR data sets were combined using logistic regression in a unique 5-gene assay and the resulting predicted probabilities were subjected to ROC curve analysis. Sensitivity, specificity, p-value and AUC values are enclosed.
Figure 4
Figure 4. DR5 and IAPs gene expression in KRAS-mutant (KRAS-G13D, KRAS-G12D, KRAS-G12V) and KRAS wild-type CRC tissues.
(A) Box plots show the significant over-expression of DR5 in CRCs regardless of KRAS mutation status, (B) Box plots show significant down-regulation of cIAP1 in CRC tissues regardless of KRAS mutation status, (C) Box plots show the significant over-expression of BIRC5/Survivin in KRAS wild-type CRC tissues, but not in KRAS-mutant ones, (D) Box plots show significant down-regulation of cIAP2 in KRAS-mutant CRC tissues, but not in KRAS wild-type ones, (E,F) Box plots show that the deregulation of XIAP and DR4 mRNA expression in CRC is not significant in KRAS mutation status sybgroups of patients.
Figure 5
Figure 5. Analysis of protein expression and histological staining.
Protein analysis for DR5 (A), BIRC5/Survivin (B), cIAP1 (C), cIAP2 (D) and DR4 (E) by immunohistochemistry in human colon tumors. Strong immunoreactivity is shown for DR5, DR4 in T167 and BIRC5/Survivin in T197. Moderate immunoreactivity is shown for BIRC5/Survivin in T145 and DR4 in T187. Mild immunoreactivity is shown for cIAP1 and cIAP2. Original magnification was 200X, except for T131, T127 for cIAP1, T24 for cIAP2 and T187, that was 100X. Arrows indicate normal mucosa. T: tumor. Haematoxylin-eosin (H,E) stained slides from the taken samples were used to confirm the percentage of tumor (F). Original magnification was 25X.

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