Influence of a 5-bp Indel Polymorphism at Promoter of the GAS5 lncRNA and Risk of Breast Cancer.
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SUBMITTER: Sharifi R
PROVIDER: S-EPMC8046312 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The growth arrest special 5 (GAS5), as a research hotspot of long noncoding RNAs (lncRNAs), has been reported to be associated with colorectal cancer (CRC). However, the association between polymorphisms in GAS5 and the risk of CRC was not clear. In the present study, a case-control study in 1078 CRC patients and 1175 matched healthy controls was performed to evaluate the association between the potential functional genetic variants in GAS5 and the risk of CRC. PCR-TaqMan, qPCR, dual-luciferase assay, electrophoretic mobility shift assay (EMSA), flow cytometry, migration and invasion assays were performed to evaluate the function of polymorphism. Results showed that subjects carrying the rs55829688 CT/TT genotypes had a significantly higher risk of CRC when compared with the CC genotype. Further qPCR assay confirmed that the CRC tissues with rs55829688 CT/TT genotypes had a higher GAS5 mRNA expression level. The dual-luciferase assay, qPCR and EMSA assay revealed that rs55829688 T>C polymorphism could decrease the expression level of GAS5 by impacting the binding ability of the transcription factor Yin Yang-1 (YY1) to the GAS5 promoter region. The expression of apoptosis-related proteins were detected by Western blot. Further, flow cytometry, migration, and invasion experiments showed that GAS5 repressed apoptosis and increased invasion and migration capability of CRC cells. Taken together, our findings provided evidence that the rs55829688 variant in the GAS5 promoter was associated with the risk of CRC and decreased expression of GAS5 by affecting the binding affinity of the transcription factors YY1 to GAS5.
| S-EPMC6465203 | biostudies-literature
Project description:ObjectiveThe long non-coding RNA (lncRNA) growth arrest‑specific transcript 5 (GAS5) plays an important role in various tumors, and an increasing number of studies have explored the association of the GAS5 rs145204276 polymorphism with cancer risk with inconclusive results.MethodsPubMed, Medline, EMBASE, Cochrane databases, and Web of Science were searched, and nine studies involving 6107 cases and 7909 controls were deemed eligible. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the relationship between rs145204276 and cancer risk in six genetic models.ResultsThe pooled results suggest that the variant allele del was not associated with overall cancer risk. However, the subgroup analysis showed that allele del was significantly associated with a 22% decreased risk of gastrointestinal cancer (OR = 0.78, 95% CI: 0.72-0.85). Both sensitivity analyses and trial sequential analyses (TSA) demonstrated that the subgroup results were reliable and robust. Moreover, False-Positive Report Probability (FPRP) analysis indicated that the results had true significant correlations.ConclusionThese findings provide evidence that the GAS5 rs145204276 polymorphism is associated with the susceptibility to gastrointestinal cancer. Further studies with different ethnicities and larger sample sizes are warranted to confirm these results.
| S-EPMC8447101 | biostudies-literature
Project description:BackgroundThe association between a 4-bp indel polymorphism (rs10680577) within the distal promoter of EGLN2 and cancer risk has been investigated by several case-control studies in recent years, but investigation results were inconsistent. Thus, a systematic assessment of the association was performed based on a literature review and pooled analysis.MethodsTwo investigators independently retrieved relevant studies from PubMed, Chinese National Knowledge Infrastructure (CNKI), Embase, and Google Scholar. The fixed or random effects model was selected to calculate odds ratios (ORs) with 95% confidence intervals (CIs) based on heterogeneity level. All analyses including heterogeneity assessment, subgroup analysis, sensitivity analysis, and publication bias assessment were performed using RevMan 5.3 software and Stata 12.0 software.ResultsA total of six relevant studies with 3,406 cases and 5,147 controls were included in the final analysis. The overall pooled analysis showed that EGLN2 rs10680577 polymorphism was significantly associated with cancer risk under all genetic models. However, subgroup analysis based on cancer type showed that the polymorphism was significantly associated with the risk of digestive system cancer under all genetic models, and with the risk of lung cancer under dominant model, heterozygote comparison model, and allele comparison model. Subgroup analysis based on population sources showed a significant association in Chinese population under all genetic models.ConclusionThe present result suggests that EGLN2 rs10680577 polymorphism is associated with cancer risk, and may act as a promising predictive biomarker for cancer risk, especially in Chinese population. However, further well-designed studies are warranted to confirm these results.
| S-EPMC6785434 | biostudies-literature
Project description:ObjectivesTo further investigate how sevoflurane affects the oxidative stress injury (OSI) in patients undergoing laparoscopic cholecystectomy (LC).MethodsA prospective cohort study was carried out at Shandong Provincial Third Hospital, Jinan, China on 82 gallstone patients who underwent LC, with sevoflurane maintenance during surgery. Genotyping analysis of the rs145204276 polymorphism was performed using the TaqMan platform. Oxidative stress injury and liver injury parameters were also examined. Lipopolysaccharide (LPS)-induced macrophages, which were challenged with sevoflurane, propofol, or the lncRNA-GAS5 overexpressing plasmid, were used to evaluate the effect of Sevoflurane on lncRNA-GAS5-mediated macrophage polarization.ResultsAt TM1 and TM2, the levels of OSI markers and long noncoding (lnc) RNA-GAS5 were not obviously different, whereas at the TM3 time point, these indices were significantly different between the Del-Sevoflurane and Del-Propofol subgroups. These indices were not different between the Ins-sevoflurane and Ins-Propofol subgroups at any time point. Cell-based experiments demonstrated that Sevoflurane could increased the lncRNA-GAS5 level in LPS-induced Del-macrophages (p=0.0058), but Propofol did not have this effect (p=0.847). Both Sevoflurane and Propofol did not have the effect on lncRNA-GAS5 level in LPS-induced Ins-macrophages (p=0.321 and p=0.822, respectively).ConclusionSevoflurane maintenance can decrease OSI during LC in the Del genotype of the rs145204276 polymorphism. The Del genotype facilitates lncRNA-GAS5 up-regulation under Sevoflurane exposure and therefore decrease the extent of M1 macrophage polarization.
| S-EPMC9987708 | biostudies-literature
Project description:Polymorphisms in pre-miRNAs may affect its expression, then having effect on its target mRNAs and be associated with cancer susceptibility. In the current study, we evaluated the association of a 3-base pair (3-bp) indel polymorphism (rs57408770) in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. To further investigated the molecular mechanism underlying the correlation between rs57408770 and the risk of HCC, overexpression of pre-miR-3131 in HCC cell line was performed. Human HCC cell lines Sk-Hep-1 was obtained from Shanghai Cell Bank of Chinese Academy of Sciences on 9 December 2013.The fragment of 366bp including the insert allele of rs57408770 in pre-miR-3131 was directly synthesized and cloned into BamHI and EcoRI sites of pEGFP-N1 yielding the wild-type vector (pEGFP-N1-miR3131-WT). The mutant-type vector (pEGFP-N1-miR3131-MT) including the delete allele of rs57408770 was generated using QuikChange Lightening Site-Directed Mutagenesis Kit. The resulting constructs were verified by direct sequencing. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5μg plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000. After 24 hours of the transfection, the cells were collected for subsequent experiments.And human genome-wide gene expression profile assay was used to screen the targets of miR-3131. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5μg plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000 (Invitrogen). After 24 hours of the transfection, the cells were collected for subsequent experiments. There are 3 samples in this experiment.
2016-08-04 | E-GEOD-85123 | biostudies-arrayexpress
Project description:Polymorphisms in pre-miRNAs may affect its expression, then having effect on its target mRNAs and be associated with cancer susceptibility. In the current study, we evaluated the association of a 3-base pair (3-bp) indel polymorphism (rs57408770) in pre-miR-3131 with hepatocellular carcinoma (HCC) susceptibility in a Chinese population. Logistic regression analysis showed that the insertion allele of rs57408770 was significantly associated with an increased risk for HCC occurrence in both case-control studies. To further investigated the molecular mechanism underlying the correlation between rs57408770 and the risk of HCC, overexpression of pre-miR-3131 in HCC cell line was performed. Human HCC cell lines Sk-Hep-1 was obtained from Shanghai Cell Bank of Chinese Academy of Sciences on 9 December 2013.The fragment of 366bp including the insert allele of rs57408770 in pre-miR-3131 was directly synthesized and cloned into BamHI and EcoRI sites of pEGFP-N1 yielding the wild-type vector (pEGFP-N1-miR3131-WT). The mutant-type vector (pEGFP-N1-miR3131-MT) including the delete allele of rs57408770 was generated using QuikChange Lightening Site-Directed Mutagenesis Kit. The resulting constructs were verified by direct sequencing. For overexpression experiments, cells were cultured in 6-well plates at a density of 200 000 cells per well the day before transfection. 2.5μg plasmids of empty vector pEGFP-N1, pEGFP-N1-miR3131-WT or pEGFP-N1-miR3131-MT were transfected into the growing cells (about 80%-90% confluent) using Lipofectamine2000. After 24 hours of the transfection, the cells were collected for subsequent experiments.And human genome-wide gene expression profile assay was used to screen the targets of miR-3131.
2016-08-04 | GSE85123 | GEO
Project description:Growth arrest-specific 5 (GAS5) is a kind of long non-coding RNAs (lncRNAs). Previous studies showed that down-regulation of LncRNA-GAS5 was involved in the development of systemic lupus erythematosus (SLE). However, the regulatory mechanism of down-expressed LncRNA-GAS5 in SLE remains obscure. In this study, we aimed to investigate the association of LncRNA-GAS5 polymorphism with SLE risk. And further explore how LncRNA-GAS5 is involved in the occurrence of SLE. Here, we evaluated the relationship between the risk for the development of SLE and the 5-base pair (AGGCA/-) insertion/deletion (I/D) polymorphism (rs145204276) in the LncRNA-GAS5 promoter region. A custom 36-Plex SNPscan kit was used for genotyping the LncRNA-GAS5 polymorphisms. The LncRNA-GAS5 and miR-21 target prediction was performed using bioinformatics software. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR) were performed to assess GAS5 and miR-21 mRNA expression and PTEN protein expression. The results revealed that rs145204276 resulted in a decreased risk of SLE (DD genotypes vs II genotypes: adjusted OR = 0.538, 95% CI, 0.30-0.97, P = .039; ID genotypes vs II genotypes: adjusted OR = 0.641, 95% CI, 0.46-0.89, P = .007; ID/DD genotypes vs II genotypes: adjusted OR = 0.621, 95% CI, 0.46-0.84, P = .002; D alleles vs I alleles: adjusted OR = 0.680, 95% CI, 0.53-0.87, P = .002). A reduced incidence of renal disorders in SLE was found to be related to ID/DD genotypes and D alleles (ID/DD genotypes vs II genotypes: OR = 0.57, 95% CI, 0.36-0.92, P = .020; D alleles vs I alleles: OR = 0.63, 95% CI, 0.43-0.93, P = .019). However, no significant association of rs2235095, rs6790, rs2067079 and rs1951625 polymorphisms with SLE risk was observed (P > .05). Additionally, haplotype analysis showed that a decreased SLE risk resulted from the A-A-C-G-D haplotype (OR = 0.67, 95% CI, 0.49-0.91, P = .010). Also, patients in the SLE group showed a down-regulated expression of LncRNA-GAS5 and PTEN than the healthy volunteers; however, patients with rs145204276 ID/DD genotypes showed up-regulated expression of LncRNA-GAS5 and PTEN compared with patients carrying the II genotype. Furthermore, the miR-21 levels were considerably up-regulated in the SLE group than the healthy volunteers, and patients with rs145204276 ID/DD genotype had lower miR-21 levels than the ones with the II genotype. Thus, we found that the LncRNA-GAS5/miR-21/PTEN signalling pathway was involved in the development of SLE, where LncRNA-GAS5 acted as an miR-21 target, and miR-21 regulated the expression of PTEN. These findings indicated that the rs145204276 ID/DD genotypes in the LncRNA-GAS5 gene promoter region may be protected against SLE by up-regulating the expression of LncRNA-GAS5, which consecutively regulated miR-21 and PTEN levels.
| S-EPMC8034459 | biostudies-literature
Project description:OBJECTIVE:To investigate the role of long non-coding RNA growth arrest-specific transcript 5 (lncRNA-GAS5) in breast cancer progression and epithelial-mesenchymal transition (EMT) of the cancer cells. METHODS:Real-time quantitative PCR (qRT-PCR) was used to detect the expression of lncRNA-GAS5 in 37 pairs of breast cancer and adjacent non-tumor tissues and in parental MCF-7 cells and paclitaxel-resistant MCF-7 (MCF-7/PR) cells, and the correlation of lncRNA-GAS5 expression with the clinical stage and lymph node metastasis of breast cancer was investigated. The expressions of the genes related with cell cycle and EMT at both the mRNA and protein levels were detected using qRT-PCR, Western blotting and immunohistochemistry. The changes in the biological behaviors and morphology of breast cancer cells with either lncRNA-GAS5 knockdown or overexpression were observed. Nude mouse models were established bearing breast cancer xenografts derived from MCF-7/PR cells or MCF-7/PR cells over-expressing lncRNA-GAS5, and the inhibitory effect of paclitaxel on tumor growth was evaluated. RESULTS:The transcriptional levels of lncRNA-GAS5 were significantly lower in breast cancer tissues than in the adjacent non-tumor tissues (P<0.05), and decreased lncRNA-GAS5 expression was significantly correlated with TNM stage and lymph node metastasis of breast cancer (P<0.05). lncRNA-GAS5 expression was also significantly lowered in paclitaxel-resistant breast cancer cells and showed a positive correlation with P21 expression and a negative correlation with CDK6. MCF-7 cells during EMT presented with a lowered expression of lncRNA-GAS5, whereas lncRNA-GAS5 over-expression strongly suppressed MCF-7/PR cell migration and invasion, and increased the susceptibility of the cells to paclitaxel. In the tumor-bearing nude mouse models, lncRNA-GAS5 overexpression in the tumor cells obviously enhanced the inhibitory effect of paclitaxel on tumor growth and lung metastasis by reversing the EMT marker proteins. CONCLUSION:A decreased expression of lncRNA-GAS5 promotes lung metastasis of breast cancer by inducing EMT, suggesting the potential of lncRNA-GAS5 as a therapeutic target in breast cancer.
| S-EPMC6779650 | biostudies-literature
Project description:Background:Previous studies showed that genetic variant rs145204276 in the promoter region of GAS5 was associated with the development of human cancer including colorectal cancer and hepatocellular cancer. This study aimed to investigate the role of rs145204276 in the development of osteosarcoma (OS). Methods:132 OS patients and 1270 healthy controls were recruited for the genotyping analysis of rs145204276. Promoter methylation level of GAS5 was determined for all patients. The tumor tissues and the adjacent normal tissue were collected from 42 patients during surgery and the relative expression of GAS5 was then quantified by Real-time PCR. The Chi-square test was used to determine the difference of genotype and allele frequency between the patients and the controls. The gene expression and the percentage of methylation alleles were compared among different genotypes of rs145204276 with One-way ANOVA test. Results:Compared with the controls, patients were found to have significantly lower rate of genotype del/del (7.6% vs. 8.7%, p?=?0.024). The frequency of allele del was significantly lower in the patients than in the controls (23.5% vs. 30.1%, p?=?0.021). Compared with than patients with genotype ins/ins, those with genotype del/del had remarkably higher expression of GAS5 (0.0033?±?0.0019?vs. 0.0018?±?0.0006, p?<?0.001). Patients with genotype del/del were found to have obviously hypermethylation at the 7th CpG site as compared with those with genotype ins/ins (38.7%?±?21.1% vs. 20.5%?±?8.2%, p?<?0.001). Conclusions:The genetic variant rs145204276 is functionally associated with the susceptibility of OS, which can function as a protective factor in the incidence of OS possibly through the regulation of GAS5.
| S-EPMC6045496 | biostudies-literature
Project description:PurposeLong noncoding RNAs (lncRNAs) have been widely studied, and single nucleotide polymorphisms (SNPs) in lncRNAs are considered to be genetic factors that influence cancer susceptibility. The lncRNA GAS5, MEG3, and PCAT-1 polymorphisms are shown to be possibly associated with cancer risk. The aim of this meta-analysis was to systematically evaluate this association.MethodsStudies were selected from PubMed, Web of Science, Embase, Google Scholar, Cochrane Library, the Chinese National Knowledge Infrastructure (CNKI), and the Chinese Biomedical Literature Database (CBM) through inclusion and exclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the random-effects model or fixed-effects model to assess the association between lncRNA polymorphisms and cancer susceptibility. Metaregression and publication bias analyses were also conducted. All analyses were performed using the Stata 12.0 software.ResultsSixteen articles (covering 13750 cases and 17194 controls) were included in this meta-analysis. A significant association between SNP rs145204276 and gastric cancer risk was observed (del vs. ins: OR = 0.79, 95%CI = 0.72-0.86; del/del vs. ins/ins+del/ins: OR = 0.74, 95%CI = 0.59-0.91; del/ins vs. ins/ins: OR = 0.84, 95%CI = 0.67-1.05). For rs16901904, a decreased cancer risk was observed in three genetic models (C vs. T: OR = 0.79, 95%CI = 0.70-0.90; CC vs. CT+TT: OR = 0.49, 95%CI = 0.37-0.65; CC vs. TT: OR = 0.49, 95%CI = 0.37-0.66). No statistical significance was found in the metaregression analysis. For all of the included SNPs, no publication bias was found in all genotype models.ConclusionsThe rs145204276 SNP in lncRNA GAS5 is likely to be associated with gastric cancer risk, whereas the rs16901904 SNP in lncRNA PCAT-1 bears association with a decreased cancer risk.
| S-EPMC7142337 | biostudies-literature