A functional NKILA variant (rs2273534) drives genetic susceptibility and oncogenic progression in gastric cancer via the miR-4424/OAS2 pathway.

[OBJECTIVE] This research examines how NF-κB Interacting LncRNA (NKILA) and its functional variant rs2273534 influence gastric cancer (GC) risk, development, and prognosis, along with the molecular pathways involved.

[METHODS] 840 GC patients and 840 healthy controls participated in a case-control research. Genetic association analyses, molecular experiments (qRT-PCR, Western blot, functional assays), and bioinformatics approaches were employed. Cell-based and animal experiments were employed to validate the oncogenic role of NKILA and its regulatory axis.

[RESULTS] Carriers of the NKILA rs2273534 C allele exhibited a markedly higher susceptibility to GC (OR = 1.51, p = 0.003) and an unfavorable prognosis (HR = 1.89, p = 0.016), which was also associated with elevated NKILA expression. Elevated NKILA expression in GC tissues was associated with advanced clinicopathological characteristics. Mechanistically, NKILA promotes the expression of 5'-Oligoadenylate Synthetase 2 (OAS2) through sponging miR-4424, which in turn facilitates proliferation, migration, invasion, and EMT in GC cells. Rescue experiments confirmed that the NKILA/miR-4424/OAS2 axis is crucial for GC malignancy.

[CONCLUSIONS] The rs2273534 SNP enhances NKILA expression and drives GC progression through the NKILA/miR-4424/OAS2 axis. Our findings highlight rs2273534 as a possible indicator for GC susceptibility and prognosis, offering insights into the oncogenic mechanisms mediated by lncRNAs.