Polymorphisms in miRNA binding site: new insight into small cell lung cancer susceptibility.
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ABSTRACT:
SUBMITTER: Liu HY
PROVIDER: S-EPMC4010083 | biostudies-literature | 2011 Oct
REPOSITORIES: biostudies-literature
Publications
Polymorphisms in miRNA binding site: new insight into small cell lung cancer susceptibility.
Acta pharmacologica Sinica 20110829 10
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Project description:AimTo explore the association between COX-2 polymorphisms and non-small cell lung cancer (NSCLC) susceptibility.MethodsWe collected fasting peripheral venous blood from 60 cases with NSCLC and 62 healthy controls through physical examinations, and applied PCR-RFLP to analyze COX-2 polymorphisms of two groups.ResultsWith respect to detecting COX-2 rs689466 and rs5275 polymorphisms, the distribution frequency of mutant genotype AA of COX-2 rs689466 in case group was higher than that in control group, which possessed significant difference between two groups (P<0.05). Carriers with AA genotype were 4.05 times at risk of NSCLC than those with GG genotype (P = 0.04, OR=4.05, 95% CI=1.14-14.43). The distribution of mutant genotype CC of COX-2 rs5275 was different between two groups, and carriers with genotype CC were at 5.70 times higher risk of NSCLC than those with genotype TT. After corrected by sex, gender, smoking and drinking factors, AA genotype of COX-2 rs689466 and CC genotype of COX-2 rs5275 still contributed to increased risk of NSCLC (OR=4.22, 95% CI=1.10-16.17, OR=6.95, 95% CI=1.27-38.11). After analyzed of linkage disequilibrium (LD) and haplotypes of alleles in two SNPs, the distribution frequency of A-C haplotype in case group was higher than that in control group, with significant difference between two groups (P<0.05). After corrected by sex, gender, smoking and drinking factors, statistical difference was still found in the total distribution of A-C haplotype between two groups (P=0.03, OR=6.11, 95% CI=1.16-32.2).ConclusionsCOX-2 rs689466 and rs5275 polymorphisms may be related to NSCLC susceptibility. And A-C haplotype might be a susceptibility haplotype for NSCLC.
| S-EPMC4440144 | biostudies-literature
Project description:BACKGROUND:Tumor necrosis factor superfamily member 15 (TNFSF15) is closely related to tumorigenesis and development. This study aimed to investigate the correlations between TNFSF15 polymorphisms and genetic susceptibility to lung cancer. METHODS:This case-control study included 209 small cell lung cancer patients (SCLC), 340 non- small cell lung cancer patients (NSCLC) and 460 health controls. TNFSF15-638 A > G and - 358 T > C polymorphisms were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression. RESULTS:Our results showed that subjects carrying the TNFSF15-638GG genotype or -358CC genotype were more likely to develop SCLC (-638GG, OR = 1.84, 95%CI = 1.13-2.99; -358CC, OR = 2.44, 95%CI = 1.46-4.06), but not NSCLC (P > 0.05). In stratified analysis, -638GG genotype was related to SCLC among males (OR = 1.95, 95%CI = 1.09-3.45, P = 0.023) and older patients (OR = 2.93, 95%CI = 1.44-8.68, P = 0.006). However, -358CC genotype was associated with SCLC among females (OR = 8.42, 95%CI = 2.22-31.89, P = 0.002) and older subjects with OR (95%CI) of 11.04 (3.57-34.15) (P < 0.001). Moreover, TNFSF15 -358CC was linked with a higher risk of SCLC among non-smokers (OR = 2.54, 95%CI = 1.20-5.35, P = 0.015) but not among smokers (OR = 1.88, 95%CI = 0.92-3.84, P = 0.086). CONCLUSION:These findings highlight the importance of TNFSF15 polymorphisms in the development of SCLC.
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Project description:The etiology of lung cancer is still incompletely understood. Previous studies have suggested the association between IL-21 polymorphisms and autoimmune diseases, however, little is known about its role in lung cancer susceptibility. Here, we investigated the role of two SNPs of IL-21 gene in a cohort of non-small cell lung cancer (NSCLC) patients. A total of 128 NSCLC patients and 156 healthy controls were genotyped. Multivariate logistic regression was used to analyze the association between IL-21 polymorphisms and NSCLC risk. Our data showed that both rs907715 and rs2221903 were significantly associated with lung cancer susceptibility, and patients carrying rs907715A (P = 0.007, adjusted OR = 0.60, 95% CI = 0.42-0.87) or rs2221903G (P = 0.020, adjusted OR = 0.52, 95% CI = 0.30-0.90) allele had a decreased risk of NSCLC. Further study identified that the association between IL-21 polymorphisms and NSCLC risk was limited to lung adenocarcinoma. Haplotype analysis revealed that the AG (P = 0.006, OR = 0.072 95% CI = 0.011-0.451) and AA (P = 0.022, OR = 0.657, 95% CI = 0.458-0.941) haplotypes of rs907715/rs2221903 were associated with a decreased risk of NSCLC, whereas the GA (P = 0.0001, OR = 1.932, 95% CI = 1.378-2.710) haplotype was associated with an increased risk. In conclusion, our study demonstrates the association between IL-21 polymorphisms (rs907715 and rs2221903) and NSCLC risk in a Chinese Han population, indicating their potential role in lung cancer detection and treatment.
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Project description:BackgroundBone morphogenetic protein receptor I B (BMPR1B) is a transmembrane receptor mediating TGF-? signal transduction. Recent studies indicate a tumor suppressor role for BMPR1B in ovarian cancer. Polymorphism at BMPR1B 3'UTR within the miR-125b binding site alters its binding affinity toward the miRNA, which may result in insufficient post-transcriptional repression.MethodsSingle-nucleotide polymorphisms rs1970801, rs1434536, and rs11097457 near the miR-125b binding site in BMPR1B were genotyped by Taqman assay on 193 endometriosis patients and 202 healthy controls. BMPR1B and CA125 levels in ectopic endometrial tissues were evaluated by quantitative PCR and immunohistochemistry. Luciferase reporter assay was utilized to verify regulatory roles of BMPR1B 3'UTR with allelic variants of rs1434536 in a cell line model. Cell proliferation and migration were recorded, while expression of BMPR1B, CA125, glucocorticoid receptor (GCCR) and IL-1? were measured by quantitative PCR in endometrial cells transfected with wild-type or mutated miR-125b.ResultsThis study found two endometriosis-associated SNPs, rs1434536 (P?=?0.010) and rs1970801 (P?=?0.0087), located within and next to a miR-125b binding site on BMPR1B. Interestingly, patients with homozygous variant alleles at rs1434536 showed significantly lower serum CA125 levels. Immunohistochemistry staining further confirmed inverse correlation between BMPR1B and CA125 levels in three rs1434536 genotypes. Cell assays demonstrated the variant allele of rs1434536 up-regulating BMPR1B at both mRNA and protein levels, which negatively correlated with CA125 and IL-1? levels. Disruption of the binding between miR-125b and BMPR1B hampered abnormal cell proliferation.ConclusionsSNPs of BMPR1B within and next to the miR-125b binding site manifested strong correlation with endometriosis development in a Taiwanese cohort. Disrupting the binding of miR-125b toward BMPR1B would increase protein expression, diminishing abnormal cell proliferation as well as serum and cellular CA125 levels. Genetic variation at the miR-125b binding site may play functional roles to protect against endometriosis progression.
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Project description:Studies have reported that B- and T-lymphocyte attenuator (BTLA) polymorphisms may be associated with the risk to different cancers. However, the correlation between those variations and non-small-cell lung cancer (NSCLC) is still unclear. A total of 1,003 NSCLC patients and 901 noncancer controls were recruited in the study, to confirm the association of variations in BTLA gene with the risk of NSCLC. The SNPscan™ genotyping assay was used to obtain the genotypes of the four BTLA polymorphisms (BTLA rs1982809 G>A, rs16859629 T>C, rs2171513 G>A, and rs3112270 A>G). It was found that BTLA rs1982809 polymorphism reduced the risk of NSCLC (GA vs. GG: adjusted odds ratio (OR) = 0.81, 95%confidence interval (CI) = 0.66-0.99, and P = 0.043). However, the BTLA rs16859629, rs2171513, and rs3112270 polymorphisms showed no significant association between NSCLC patients and controls in overall comparison. In subgroup analyses, we found that BTLA rs1982809 polymorphism reduced the risk of NSCLC (nonsquamous cell carcinoma: GA vs. GG: adjusted OR = 0.79, 95%CI = 0.64-0.97, and P = 0.026; AA/GA vs. GG: adjusted OR = 0.81, 95%CI = 0.66-0.99, and P = 0.037; ≥59 years: GA vs. GG: P = 0.036; never alcohol consumption: GA vs. GG: P = 0.013; GA/AA vs. GG: P = 0.016; body mass index (BMI) ≥ 24 kg/m2: GA vs. GG: P = 0.030; GA/AA vs. GG: P = 0.041). The BTLA rs16859629 polymorphism increased the risk of the development of squamous cell carcinoma (CC vs. TT: adjusted OR = 9.85, 95%CI = 1.37-71.03, and P = 0.023; CC vs. TT/TC: adjusted OR = 9.55, 95%CI = 1.32-68.66, and P = 0.025). Taken together, the findings of the present suggest that BTLA rs1982809 and rs16859629 polymorphisms may influence the susceptibility to NSCLC in the Chinese population.
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Project description:A growing number of studies have shown that microRNAs (miRNAs) can exert oncogenic or tumor suppressor activities in a variety of cancers, including lung cancer. Given their presence in exosome preparations, microRNA molecules may in fact participate in exosomal intercellular transfers and signaling. In the present study, we examined the profile of 25 circulating exosomal microRNAs in ostensibly healthy controls compared to patients with squamous cell lung cancers (SQCLC) or lung adenocarcinomas (LUAD). Eight miRNAs, namely, miR-21-5p, miR-126-3p, miR-210-3p, miR-221-3p, Let-7b-5p, miR-146a-5p, miR-222-3p, and miR-9-5p, were highly enriched in the cohort and selected for further analyses. All miRNAs were readily detected in non-small cell lung cancer (NSCLC) patients of both sexes at all cancer stages, and their levels in exosomes correlated with the clinicopathological characteristics of tumors. Thus, the presence of these miRNAs in circulating exosomes may contribute to the regulation of oncogenic activity in patients with NSCLC.
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Project description:IntroductionSmall cell lung cancer (SCLC) is characterized by poor prognosis and challenging diagnosis. Screening in high-risk smokers results in a reduction in lung cancer mortality, however, screening efforts are primarily focused on non-small cell lung cancer (NSCLC). SCLC diagnosis and surveillance remain significant challenges. The aberrant expression of circulating microRNAs (miRNAs/miRs) is reported in many tumors and can provide insights into the pathogenesis of tumor development and progression. Here, we conducted a comprehensive assessment of circulating miRNAs in SCLC with a goal of developing a miRNA-based classifier to assist in SCLC diagnoses.MethodsWe profiled deregulated circulating cell-free miRNAs in the plasma of SCLC patients. We tested selected miRNAs on a training cohort and created a classifier by integrating miRNA expression and patients' clinical data. Finally, we applied the classifier on a validation dataset.ResultsWe determined that miR-375-3p can discriminate between SCLC and NSCLC patients, and between SCLC and Squamous Cell Carcinoma patients. Moreover, we found that a model comprising miR-375-3p, miR-320b, and miR-144-3p can be integrated with race and age to distinguish metastatic SCLC from a control group.DiscussionThis study proposes a miRNA-based biomarker classifier for SCLC that considers clinical demographics with specific cut offs to inform SCLC diagnosis.
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