Variant of SNP rs1317082 at CCSlnc362 (RP11-362K14.5) creates a binding site for miR-4658 and diminishes the susceptibility to CRC

Abstract

Genome-wide association studies (GWAS) have identified several loci harboring variants that affected the risk of colorectal cancer; however, the specific mechanisms by which germline variation influenced the tumorigenesis of colorectal cancer (CRC) remains unrevealed. We found the T>C variant of rs1317082, locating at the exon 1 of lncRNA RP11-362K14.5 (CCSlnc362), was predicted to be a protective locus for cancer. However, the specific role of CCSlnc362 and the interaction between CCSlnc362 and rs1317082 variation in colorectal cancer and its mechanisms remain unclear. Here we explored the expression and function of CCSlnc362 in CRC cells and tissues. We found lncRNA CCSlnc362 expression was significantly increased in CRC samples. Follow-up functional experiments elucidated that downregulation of CCSlnc362 inhibited cell proliferation, arrested cell cycle, and promoted apoptosis in CRC cells. The T>C variant of rs1317082 at CCSlnc362 exon 1 created a binding site for miR-4658 to reduce the expression of CCSlnc362 and thus decreased the susceptibility to CRC. Our findings have provided supporting evidence for the protective role of rs1317082 variation and the potential oncogenic role of lncRNA CCSlnc362 in CRC. The data shed new light on the relationship between germline variation, miRNAs, and lncRNAs and opened a new avenue for targeted therapy in CRC.

Functional Polymorphisms in DNA Repair Genes Are Associated with Sporadic Colorectal Cancer Susceptibility and Clinical Outcome

“…Several studies provided evidence that single nucleotide polymorphisms (SNPs) in DNA repair genes could alter DNA repair function, modulate its capacity, and thus induce genetic instability or unregulated cell growth and cancer [7,8,9]. In the last decade, while association studies (including genome-wide) have identified multiple SNPs involved in CRC susceptibility, none have been validated as biomarkers for clinical use [10,11,12,13,14]. Furthermore, most of the anticancer agents are targeted to induce DNA damage, which overwhelms the cellular DNA repair capacity and thus leads to apoptosis.…”

Associations between lncRNA‐related polymorphisms and hepatocellular carcinoma risk: A two‐stage case–control study

“…[38][39][40][41] For example, the T > C variant of rs1317082 at lncRNA CCSlnc362 creates a binding site for miR-4658 to reduce the expression of CCSlnc362 and thus decreases susceptibility to CRC. 42 Target SNPs in our research have been demonstrated to play a role in susceptibility to digestive system tumors in previous studies. However, studies investigating the specific functions and potential mechanisms of these SNPs or their related lncRNAs in HCC were lacking until now.…”

“…A large number of lncRNAs have been found important for cancer initiation and progression, 35–37 and increasing evidence indicates that SNPs can potentially modulate lncRNA secondary structure, influence its stability, expression, interactive properties, and regulatory functions, possibly by creating binding sites for or disrupting interaction with other RNAs or proteins 38–41 . For example, the T > C variant of rs1317082 at lncRNA CCSlnc362 creates a binding site for miR‐4658 to reduce the expression of CCSlnc362 and thus decreases susceptibility to CRC 42 . Target SNPs in our research have been demonstrated to play a role in susceptibility to digestive system tumors in previous studies.…”

MAGI2‐AS3 rs7783388 polymorphism contributes to colorectal cancer risk through altering the binding affinity of the transcription factor GR to the MAGI2‐AS3 promoter

“…For example, Shaker et al reported that the lncRNA HULC SNP rs7763881 A > C decreased the susceptibility of CRC by reducing the oncogenic HULC level 37 . lncRNA RP11‐362K14.5 SNP rs1317082 T > C reduced the expression of CCSlnc362 by creating a bind site for miR‐4658, thus decreased the risk of CRC 38 . A novel SNP rs10845671, locating in lncRNA RP11‐392P7.6 promoter region, was associated with the susceptibility of CRC 39 .…”