Acidic microenvironment-induced LAMC2 expression promotes proliferation, migration, and pathway regulation in non-small cell lung cancer cells.

[OBJECTIVE] This study aims to investigate the regulatory mechanism by which the acidic microenvironment modulates LAMC2 expression in non-small cell lung cancer (NSCLC) and to elucidate its roles in tumor cell proliferation, migration, invasion, and associated signaling pathways, thereby providing a theoretical foundation for targeted lung cancer therapies.

[METHODS] A cohort of 104 pathologically confirmed NSCLC patients treated at a designated hospital from January 2018 to December 2021 was enrolled. RNA-seq data from the TCGA database were analyzed to evaluate LAMC2 expression differences and prognostic implications using the GEPIA2 tool. assays assessed the acidic microenvironment's impact on LAMC2 expression, with functional evaluations of LAMC2 overexpression and knockdown on cellular behaviors.

[RESULTS] The LAMC2 mRNA levels were elevated across multiple tumor types and correlated with unfavorable prognoses in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). The acidic microenvironment significantly upregulated LAMC2 expression through HIF-1α-mediated transcriptional activation. LAMC2, in turn, promoted NSCLC cell proliferation, migration, and invasion by activating the PI3K/Akt signaling pathway and inducing epithelial-mesenchymal transition (EMT). Clinically, a high LAMC2 expression was associated with poor tumor differentiation, advanced TNM staging, and reduced 3-year survival rates. Moreover, LAMC2 positively correlated with immune checkpoint molecules (e.g., PD-L1, CTLA-4), implying its involvement in immune evasion.

[CONCLUSION] The acidic microenvironment upregulates LAMC2 via HIF-1α-mediated transcriptional regulation and lactate accumulation, thereby driving malignant progression in NSCLC. Elevated LAMC2 levels are linked to enhanced proliferation, migration, invasion, and dismal patient outcomes, underscoring its potential as a therapeutic target for precision oncology.