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Association between polymorphism in the promoter region of lncRNA GAS5 and the risk of colorectal cancer.

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6465203 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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.

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Association between polymorphism in the promoter region of lncRNA GAS5 and the risk of colorectal cancer.

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