Abstract
Long non-coding RNAs (lncRNAs) play key roles in colorectal carcinogenesis. Here, we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis. First, we identified rs6695584 as the causative SNP in 1q41 locus. The A>G mutation of rs6695584 created a protein-binding motif of BATF, altered the enhancer activity, and subsequently activated lncSLCC1 expression. Further validation in two independent CRC cohorts confirmed the upregulation of lncSLCC1 in CRC tissues, and revealed that increased lncSLCC1 expression was associated with poor survival in CRC patients. Mechanistically, lncRNA-SLCC1 interacted with AHR and transcriptionally activated HK2 expression, the crucial enzyme in glucose metabolism, thereby driving the glycolysis pathway and accelerating CRC tumor growth. The functional assays revealed that lncSLCC1 induced glycolysis activation and tumor growth in CRC mediated by HK2. In addition, HK2 was upregulated in colorectal cancer tissues and positively correlated with lncSLCC1 expression and patient survival. Taken together, our findings reveal a risk SNP-mediated oncogene lncRNA-SLCC1 promotes CRC through activating the glycolysis pathway.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancerrelated deaths globally
The causal single-nucleotide polymorphisms (SNPs) rs6695584 is associated with CRC survival and regulates lncSLCC1 expression as an enhancer As reported, rs6687758 has been proven to be a risk lead SNP associated with CRC in a large meta-analysis based on genome-wide association studies (GWAS) studies.[11]
The results showed that patients with G allele (GG+GA) were associated with shorter 3-year overall survival than those with AA genotype, which revealed the role of the risk SNP rs6695584 in the progression of CRC
Summary
Colorectal cancer (CRC) is the second leading cause of cancerrelated deaths globally. More than 1.8 million new cases and 881,000 deaths are estimated to occur in the world in 2018.1. Several risk factors have been proven to contribute to the initiation and development of CRC, among which the genetic heritability of CRC has been estimated at 12–35%.6,7. The genome-wide association studies (GWAS) have provided much information for genetic predisposition to CRC, and have discovered over 50 independent single-nucleotide polymorphisms (SNPs) associated with CRC in both European and Asian populations.[8] most of the loci are located in non-coding regions; the biological functions of these risk
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