Polymorphisms of survivin and its protein expression are associated with colorectal cancer susceptibility in Chinese population.
ABSTRACT: To investigate the association of survivin -31G/C, -141G/C, and -241T/C polymorphisms with colorectal cancer (CRC) susceptibility and explore the mechanisms of the survivin polymorphism in CRC development. A case-control study was conducted of 275 CRC cases and 270 healthy controls. Polymorphisms of survivin -31G/C, -141G/C, and -241T/C were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Survivin and Ki-67 expression was analyzed by immunohistochemistry by the Envision technique for the paraffin sections of 152 CRC. It showed that the -31G/C genotype and allele distribution were significantly different between the CRC cases and controls. The -31CC genotype and -31C allele were over-represented among the CRC cases. Compared with the CC genotype, the GC and GG genotypes had a significantly decreased risk of CRC (p=0.015). Survivin and Ki-67 expression of patients with the CC genotype was significantly higher than the patients with the GC and GG genotypes. In addition, a significantly positive correlation was found between expression of Survivin and Ki-67. There were no significant difference of the -141G/C and -241T/C polymorphism distributions among cases and controls. Survivin 31G/C may adjust the Survivin expression, and it might contribute to a risk of developing CRC.
Project description:Survivin can affect the progression of infection and is considered as a marker of various malignancies. The aim of the study was to investigate the possible association of gene polymorphisms of survivin (-<i>1547A/G</i>, -<i>644C/T</i>, -<i>625 C/G</i>, -<i>241C/T</i>, -<i>31G/C</i>, -<i>141G/C</i>) and chronic hepatitis B infection in Iranian patients. The genotypes of survivin SNPs were investigated by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method using 100 chronic HBV infected patients (HBV), 40 spontaneously recovered HBV subjects and 100 healthy controls (C). Serum level of survivin was determined using ELISA method. The -<i>1547G</i>, -<i>625C</i>, -<i>241T</i> and -<i>31C</i> alleles were associated with increased susceptibility to chronic hepatitis B infection (<i>P</i> = 0.001, <i>P</i> < 0.001, <i>P</i> = 0.003 and <i>P</i> < 0.001 respectively). Chronic HBV patients with -<i>625CC</i>, -<i>241TT</i> and -<i>31CC</i> genotypes had higher levels of survvin. Survivin -<i>1547A/G</i>, -<i>625 C/G</i>, -<i>241C/T</i> and -<i>31G/C</i> gene polymorphisms may be associated with chronic HBV susceptibility in Iranian HBV patients.
Project description:<h4>Background</h4>Emerging evidence showed that common functional -31G>C polymorphism (rs9904341 G>C) in the promoter region of the survivin gene is involved in the regulation of survivin expression, thus increasing an individual's susceptibility to gastrointestinal tract (GIT) cancer; but individually published results are inconclusive. The aim of this systematic review and meta-analysis was to derive a more precise estimation of the association between survivin -31G>C polymorphism and GIT cancer risk.<h4>Methods</h4>A literature search of PubMed, Embase, Web of Science and CBM databases was conducted from inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.<h4>Results</h4>Nine case-control studies were included with a total of 2,231 GIT cancer cases and 2,287 healthy controls. The results indicated that survivin -31G>C polymorphism was associated with increased risk of GIT cancer. In the stratified analysis by cancer types, significant associations were observed between survivin -31G>C polymorphism and increased risk of colorectal and gastric cancers. However, the lack of association of survivin -31G>C polymorphism with esophageal cancer risk may be due to a lack of a sufficient number of eligible studies and the influence of different genetic and environmental factors.<h4>Conclusion</h4>Results from the current meta-analysis suggests that survivin -31G>C polymorphism might increase the risk of GIT cancer, especially among gastric and colorectal cancers.
Project description:Survivin has been identified as an apoptosis inhibitor and a key regulator of mitosis. A common polymorphism (-31G>C) at the survivin promoter has been extensively studied in various cancers and reported to influence survivin expression. We hypothesize that polymorphisms in the survivin promoter are associated with clinical outcomes of patients with ovarian cancer. In this study, we genotyped all of five common and independent (r(2) < 0.25 for all LD) survivin promoter polymorphisms (-1547A/G [rs3764383], -644C/T [rs8073903], -625C/G [rs8073069], -241C/T [rs17878467], and -31G/C [rs9904341]) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method. We found that -1547A/G and -31G/C were significantly associated with age of disease onset. Compared with patients with the -1547GG genotype, the -1547AA genotype showed a significantly younger age of disease onset (58.8 years vs. 70.1 years; P = 0.001); the -31CC genotype had a decrease, though not significant, in the age of disease onset, compared with patients with the -31GG genotype (57.1 years vs. 62.8 years; P = 0.058). The numbers of -1547A and -31C alleles were associated with a decrease in age of onset in an allele-dose response manner (P(trend) = 0.001 and 0.026, respectively). However, no association was found between survivin polymorphisms and patients' prognosis, except for -625C/G SNP in 37 patients with a persistent disease. The findings suggest that the promoter variants of survivin may have an effect on age of onset of ovarian cancer. Validation studies with larger sample sizes are warranted.
Project description:BACKGROUND: Survivin is an inhibitor of apoptosis protein and is involved in the occurrence and progression of human malignancies. Recently, a functional polymorphism (-31G>C, rs9904341) in the promoter of survivin has been shown to influence its expression and confer susceptibility to different types of cancer. The present study was aimed to investigate whether the polymorphism also influences susceptibility and progression of renal cell cancer (RCC) in a Chinese population. METHODS: We genotyped this polymorphism using the TaqMan assay in a case-control study comprised of 710 RCC patients and 760 controls. The logistic regression was used to assess the genetic association with occurrence and progression of RCC. RESULTS: Compared with the genotypes containing G allele (GG and GC), we found a statistically significant increased occurrence of RCC associated with the CC genotype [P?=?0.006, adjusted odds ratio (OR)?=?1.38, 95% confidence interval (CI)?=?1.08-1.76]. The polymorphism was associated with risk of developing advanced stage (OR?=?2.02, 95%CI?=?1.34-3.07) and moderately differentiated (OR?=?1.75; 95%CI?=?1.20-2.54) RCC. Furthermore, the patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease (P(trend)?=?0.003). Similar results were also observed when we restricted the analysis to clear cell RCC, a major histological type of RCC. CONCLUSIONS: Our results suggest that the functional -31G>C polymorphism in the promoter of survivin may influence the susceptibility and progression of RCC in the Chinese population. Large population-based prospective studies are required to validate our findings.
Project description:Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin -31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin -31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin -31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations.
Project description:APC mutations initiate most colorectal cancers (CRCs), but cellular mechanisms linking this to CRC pathology are unclear. We reported that wild-type APC in the colon down-regulates the anti-apoptotic protein survivin, and APC mutation up-regulates it, explaining why most CRCs display survivin overexpression and apoptosis inhibition. However, it does not explain another hallmark of CRC pathology--increased mitotic figures and cell proliferation. Because survivin activates aurora-B kinase (ABK) in vitro, catalyzing mitosis, we hypothesized that in normal colonic crypts, APC controls ABK activity, while in neoplastic APC-mutant crypts, ABK activity is up-regulated, increasing mitosis. We quantitatively mapped intracryptal distributions of survivin, ABK, and markers of activated downstream signaling and mitosis (INCENP, phospho-histone-H3, phospho-centromere-protein-A). In normal crypts, gradients for these markers, ABK:survivin:INCENP complexes, and ABK activity were highest in the lower crypt (inverse to the APC gradient). In neoplastic crypts that harbor APC mutations, proliferating (Ki-67+) cells and cells expressing survivin, ABK, and phospho-histone-H3 were distributed farther up the crypt. Hence, as cells migrate up neoplastic crypts, transitions between cell phenotypes (eg, from stem to proliferating) appear delayed. In CRC cell lines, increasing wild-type APC, inhibiting TCF-4, or decreasing survivin expression down-regulated ABK activity. Thus, APC mutation-induced up-regulation of the survivin/ABK cascade can explain delayed crypt cell maturation, expansion of proliferative cell populations (including mitotic figures), and promotion of colon tumorigenesis.
Project description:Survivin is a member of the apoptosis inhibitor protein family and its polymorphisms may lead to susceptibility to cancer. The aim of this study was to investigate the possible association of c.-31G>C (rs9904341), c.454G>A (rs2071214), c.*148T>C (rs2239680) and c.*571T>C (rs1042489) polymorphisms of survivin gene with prostate cancer risk and provide some justification using in silico analysis. The 157 men with prostate cancer and 145 healthy controls were included in a case-control study. The studied polymorphisms were genotyped using PCR-RFLP method. An in silico approach was employed to show the possible effects of the polymorphisms on the survivin gene function. The study revealed that there are significant associations between c.-31CC genotype (OR= 2.29, 95 % CI= 1.20-4.37, p= 0.012), c.-31C allele (OR= 1.62, 95 % CI= 1.17-2.26, p= 0.004), c.454AG genotype (OR= 2.03, 95 % CI= 1.02-4.04, p= 0.043), and c.*148C allele (OR= 1.49, 95 % CI= 1.04-2.15, p= 0.031) with prostate cancer. Using stratified analysis, we found also significant effects of age distribution on the association of c.-31G>C with prostate cancer risk (OR= 2.10, 95 % CI= 1.08-4.10, p= 0.030). Also as a preliminary study, it was shown that smoking status has significant effects on the association of c.-31G>C (OR= 1.94, 95 % CI= 1.08-3.49, p= 0.027) and c.*148T>C (OR= 2.60, 95 % CI= 1.47-4.60, p= 0.001) polymorphisms with prostate cancer risk. Finally, in silico analysis revealed that c.-31G>C, which is located in a CpG island of the promoter may change transcriptional regulation of survivin gene and c.454G>A and *148T>C could affect protein structure and possible miRNA interaction with 3'-UTR of survivin transcript respectively. According to the results, c.-31G>C, c.454G>A, and c.*148T>C polymorphisms could be genetic risk factors for prostate cancer in an Iranian population. However, further studies with larger sample size and different ethnicities are required to obtain more comprehensive results.
Project description:Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism to promote malignant transformation of colorectal cancer (CRC) and protect CRC cells against apoptosis. Recently, the analysis of GRP78 polymorphisms has already determined that GRP78 rs391957 polymorphism could predict clinical outcome in CRC patients. Thus, we tested whether GRP78 polymorphisms are related to the risk of CRC. In this study, we detected two GRP78 polymorphisms (rs391957 (C>T) and rs430397 (G>A)) in 414 CRC cases and 502 hospital-based cancer-free healthy controls in Southwest China using a polymerase chain reaction-restriction fragment length polymorphism technique. Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of CRC (odds ratio (OR)?=?1.39, 95% confidence interval (CI)?=?1.06-1.83 for CT genotype and OR?=?2.10, 95% CI?=?1.06-4.14 for TT genotype, respectively). In CRC cases, the variant T allele was significantly associated with tumor invasion stage (P?=?0.030), but not with status of lymph nodes metastasis (P?=?0.052). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of CRC (OR?=?1.63, 95% CI?=?1.23-2.15 for GA genotype and OR?=?2.92, 95% CI?=?1.23-6.94 for AA genotype, respectively). The rs430397 polymorphism was not associated with the clinicopathological characteristics of CRC. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as markers to predict the risk of CRC.
Project description:Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and Alpha B-crystallin (CRYAB) protein has been identified as a prognostic biomarker for CRC. We evaluated CRYAB C-802G (rs14133)polymorphism in association with CRC risk and survival in Chinese population. We genotyped for CRYAB C-802G (rs14133), A-1215G (rs2228387) and intron 2 (rs2070894), and assessed their associations with CRC in a case-control study of 441 CRC cases and 500 healthy controls. We also analyzed this polymorphism in relation to overall survival in CRC patients. A significantly different frequency distribution was found in CRYAB C-802G genotypes, but not in A-1215G and intron2 genotypes, between the cases and the controls. Under multivariable logistic regression adjusted for age and gender, CG/GG genotype carriers were associated with increased risk of CRC (OR 1.754, 95% CI 1.338-2.301, P?<?0.001) when compared with CC genotype carriers. Multivariate Cox proportional hazards model showed that patients with CG/GG genotype had significant shorter survival time than those with CC genotype, after adjustment for gender and TNM stage (HR 2.347, 95% CI 1.719-3.204, P?<?0.001), and after adjustment for gender and tumor grade (HR 2.871, 95% CI 2.121-3.887, P?<?0.001), respectively. Our results demonstrated that CG/GG at CRYAB C-802G is correlated with CRC susceptibility and this polymorphism may be an useful marker for clinical outcome of CRC.
Project description:Poly (ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and are involved in a variety of biological processes. PARP6 is a novel member, and our previous findings suggest that PARP6 may act as a tumor suppressor via suppressing cell cycle progression. However, it is still unclear that PARP6 function besides growth suppression in colorectal cancer (CRC). In this study, we examined tumor suppressive roles of PAPR6 in CRC cells both in vitro and in vivo. We found that PARP6 inhibited colony formation, invasion and migration as well as cell proliferation. Moreover, ectopic overexpression of PARP6 decreased Survivin expression, which acts as an oncogene and is involved in apoptosis and mitosis. We confirmed the inverse correlation between PARP6 and Survivin expression in CRC cases by immunohistochemistry. Importantly, CRC cases with downregulation of PARP6 and upregulation of Survivin showed poor prognosis. In summary, PARP6 acts as a tumor suppressor via downregulating Survivin expression in CRC. PARP6 can be a novel diagnostic and therapeutic target together with Survivin for CRC.