GRIK2 drives LUAD progression via the cAMP/PKA/CREB pathway

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, and the identification of novel oncogenic drivers remains critical for improving therapeutic outcomes. Glutamate receptor subunit kainate 2 (GRIK2), a neuronal receptor component, has been implicated in tumor biology, but its role in LUAD has not been defined.

Pan-cancer analysis of TCGA datasets was conducted to assess GRIK2 expression and clinical significance, with validation in LUAD cell lines and patient specimens using qRT-PCR, Western blotting, and immunohistochemistry. Functional consequences of GRIK2 silencing in PC9 cells were examined through EdU, flow cytometry, wound-healing, and Transwell assays. In vivo tumorigenicity was evaluated using a xenograft model, and mechanistic studies involved GO/KEGG enrichment and immunoblotting.

GRIK2 was significantly upregulated across multiple tumors, with highest levels in LUAD, where its expression correlated with poor survival. Validation confirmed overexpression in cell lines and tissues. Knockdown of GRIK2 suppressed proliferation, induced apoptosis, and impaired migration and invasion in vitro, while xenograft assays demonstrated reduced tumor growth and Ki67 expression. Mechanistically, GRIK2-associated genes were enriched in glutamate receptor and cAMP signaling, and GRIK2 depletion reduced phosphorylation of PKA and CREB, implicating the cAMP/PKA/CREB axis as a downstream effector.

GRIK2 functions as an oncogenic driver in LUAD, promoting progression through cAMP/PKA/CREB signaling. These findings highlight GRIK2 as a potential biomarker and therapeutic target in LUAD.