C1RL-AS1/microRNA-424-5p/adrenoceptor β2 axis: A novel regulatory mechanism in lung adenocarcinoma associated with immune infiltration and prognosis

Abstract

Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, is associated with poor prognosis and limited treatment options despite advances in cancer therapy. Adrenoceptor β2 (ADRB2) has emerged as a critical gene involved in tumor immunity and progression, yet its precise role and regulatory mechanisms in LUAD remain unclear. This study analyzed ADRB2 expression, prognostic significance, and molecular alterations using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets, and explored its regulatory mechanisms and impact on tumor immunity via comprehensive genomic analyses, dual-luciferase reporter assays, murine in vivo experiments, and flow cytometry. Results showed that ADRB2 expression was significantly decreased in LUAD tissues compared with normal controls, and low expression correlated with reduced patient overall survival. Copy number deletions and DNA hypermethylation were identified as key drivers of ADRB2 suppression. Hsa-miR-424-5p directly targets both ADRB2 and C1RL-AS1, forming the novel C1RL-AS1/hsa-miR-424-5p/ADRB2 regulatory axis. ADRB2 overexpression inhibited tumor growth, enhanced immune cell infiltration, and was positively correlated with immune checkpoint markers such as PD-1 and PD-L1. These findings provide a basis for developing novel LUAD treatment strategies focusing on immune modulation through ADRB2-targeted interventions.