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.
Highlights
Colorectal cancer (CRC) is one of the most common types of cancer worldwide, with 1.36 million new cases of CRC and 694000 deaths in 2012 [1]
We found that subjects with the rs55829688 CT/TT genotypes had a significantly increased risk when compared with those with the CC genotype
Further functional study revealed that the rs55829688 T>C polymorphism may change the binding affinity of the transcription factors Yin Yang-1 (YY1) to the rs55829688 mutation region, leading to lower expression of growth arrest special 5 (GAS5), and repress the development of CRC
Summary
Colorectal cancer (CRC) is one of the most common types of cancer worldwide, with 1.36 million new cases of CRC and 694000 deaths in 2012 [1]. The current evidence points to the increasing rate of CRC in young adults less than 50 years [2] and some environmental factors, including smoking [3], drinking [4,5], and diet [6,7] can affect the risk of CRC. Studies have shown that GAS5 plays a significant role in the development of tumors including breast cancer [12], cervical cancer [13], prostate cancer [14] etc. Single nucleotide polymorphism (SNP) is the DNA sequence polymorphism caused by single nucleotide variation at the genomic level. It is the most common form of human genetic variation, accounting for more than 90% of all known polymorphisms [15]. Previous studies have shown that GAS5 polymorphisms are associated with multiple diseases [16,17,18]; the association and mechanism between GAS5 and the risk of CRC remains unclear
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