Any genes were regulated via a post-transcriptional mechanism, e.g. upregulation of placental growth factor by vascular endothelial growth factor in endothelial cells [25]. To investigate whether the CASP8 gene has a role in CRC development through a post-transcriptional regulation, we selected paired cancerous and paracancerous normal tissues from 39 patients with different CASP8 Tein E (apoE) gene to families with a higher risk of promoter genotypes, mRNA expression and quantified protein expression level (Table S1). We observed a significant lower level of CASP8 protein in cancerous tissues than paracancerous tissues (P = 0.005), although the CASP8 mRNA levels in these samples were similar (P = 0.464, Figure 5).Controls, n ( )212 (61.99)115(33.63)rs15 (4.39) 11 (3.61)187 (61.31)107 (35.08)n =118 (38.69)Cases, n ( )130 (38.01)n =DiscussionCaspase 8 (CASP8) is a well-known procurer of death signal in the apoptotic pathway that was involved in death receptor stimulation, permeabilisation of the outer mitochondrial membrane and release of pro-apoptotic proteins into the cytosolGenotype6 bp/6 bp6 bp/deldel/del,/delabaCASP8 Polymorphisms May Not Associated with CRCFigure 1. Graphical Title Loaded From File representation of pairwise D’ and r2 values across three genetic variants in the CASP8 promoter in patients with colorectal cancer (a) and healthy individuals (b). The numbers within the squares displayed for the D’ and r2 scores (x100) for pairwise linkage disequilibrium (LD) with a red-to-white gradient reflecting higher to lower LD scores. doi:10.1371/journal.pone.0067577.gfrom mitochondria [26]. It acts as a crucial defensive barrier against malignant proliferation and tumorigenesis [7,10,27]. Previous studies have presented conflicting results regarding the potential role of genetic variants in the CASP8 gene promoter region in tumorigenesis [14,15,16,17,18,20,28,29,30]. In a pioneer study, genetic variant (rs3834129) in the CASP8 promoter region was associated with a wide range of solid cancers including lung, esophageal, gastric, colorectal, cervical, and breast cancers in Chinese populations by affecting the Sp1 transcriptional factor binding site and the CASP8 gene expression [14]. This initial finding was verified in subsequent case-control association studies in independent Chinese samples with bladder cancer [16] and coal workers’ pneumoconiosis [15]. However, several other reports failed to replicate the association between this 6 bp/del polymorphism and multiple cancers in different populations [18,30,31,32]. These inconsistent results might be explained by different genetic backgrounds of populations in different studies [33], as the frequency of 6-bp del allele was significantly different between Asian and Caucasian populations (22.4 vs. 49.1 ) [32,34]. In a recent study, Lan and coworkers [19] provided evidence that another SNP rs3769821 in the CASP8 promoter region was significantly associated with genetic risk of NHL. However, we failed to Table 4. Haplotypes of the CASP8 gene promoter variants in Han Chinese with colorectal cancer and healthy individuals.Case, Haplotypea n ( ) H1 H2 H3+ HaControl, n ( ) 363 (54.84 ) 176 (23.96 )OR (95 , CI) reference 1.05 (0.77?.42)P*318 (55.54 ) 163 (23.31 )0.77 0.118+11 (21.14 ) 138+7 (21.19 ) 1.07 (0.78?.49)Order of SNP: s3834129-rs3769821; H1: 6 bp-T, H2: 6 bp-C, H3: del-T, H4: del-C. *Unconditional logistic regression analysis adjusted for gender and age (#50 and .50 years old). doi:10.1371/journal.pone.0067577.treplicate this result in Han Chinese with.Any genes were regulated via a post-transcriptional mechanism, e.g. upregulation of placental growth factor by vascular endothelial growth factor in endothelial cells [25]. To investigate whether the CASP8 gene has a role in CRC development through a post-transcriptional regulation, we selected paired cancerous and paracancerous normal tissues from 39 patients with different CASP8 promoter genotypes, mRNA expression and quantified protein expression level (Table S1). We observed a significant lower level of CASP8 protein in cancerous tissues than paracancerous tissues (P = 0.005), although the CASP8 mRNA levels in these samples were similar (P = 0.464, Figure 5).Controls, n ( )212 (61.99)115(33.63)rs15 (4.39) 11 (3.61)187 (61.31)107 (35.08)n =118 (38.69)Cases, n ( )130 (38.01)n =DiscussionCaspase 8 (CASP8) is a well-known procurer of death signal in the apoptotic pathway that was involved in death receptor stimulation, permeabilisation of the outer mitochondrial membrane and release of pro-apoptotic proteins into the cytosolGenotype6 bp/6 bp6 bp/deldel/del,/delabaCASP8 Polymorphisms May Not Associated with CRCFigure 1. Graphical representation of pairwise D’ and r2 values across three genetic variants in the CASP8 promoter in patients with colorectal cancer (a) and healthy individuals (b). The numbers within the squares displayed for the D’ and r2 scores (x100) for pairwise linkage disequilibrium (LD) with a red-to-white gradient reflecting higher to lower LD scores. doi:10.1371/journal.pone.0067577.gfrom mitochondria [26]. It acts as a crucial defensive barrier against malignant proliferation and tumorigenesis [7,10,27]. Previous studies have presented conflicting results regarding the potential role of genetic variants in the CASP8 gene promoter region in tumorigenesis [14,15,16,17,18,20,28,29,30]. In a pioneer study, genetic variant (rs3834129) in the CASP8 promoter region was associated with a wide range of solid cancers including lung, esophageal, gastric, colorectal, cervical, and breast cancers in Chinese populations by affecting the Sp1 transcriptional factor binding site and the CASP8 gene expression [14]. This initial finding was verified in subsequent case-control association studies in independent Chinese samples with bladder cancer [16] and coal workers’ pneumoconiosis [15]. However, several other reports failed to replicate the association between this 6 bp/del polymorphism and multiple cancers in different populations [18,30,31,32]. These inconsistent results might be explained by different genetic backgrounds of populations in different studies [33], as the frequency of 6-bp del allele was significantly different between Asian and Caucasian populations (22.4 vs. 49.1 ) [32,34]. In a recent study, Lan and coworkers [19] provided evidence that another SNP rs3769821 in the CASP8 promoter region was significantly associated with genetic risk of NHL. However, we failed to Table 4. Haplotypes of the CASP8 gene promoter variants in Han Chinese with colorectal cancer and healthy individuals.Case, Haplotypea n ( ) H1 H2 H3+ HaControl, n ( ) 363 (54.84 ) 176 (23.96 )OR (95 , CI) reference 1.05 (0.77?.42)P*318 (55.54 ) 163 (23.31 )0.77 0.118+11 (21.14 ) 138+7 (21.19 ) 1.07 (0.78?.49)Order of SNP: s3834129-rs3769821; H1: 6 bp-T, H2: 6 bp-C, H3: del-T, H4: del-C. *Unconditional logistic regression analysis adjusted for gender and age (#50 and .50 years old). doi:10.1371/journal.pone.0067577.treplicate this result in Han Chinese with.
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