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.