Prognostic value and therapeutic implications of HMGA2 in EGFR-mutant non-small cell lung cancer

Background: HMGA2, an oncoprotein associated with tumor progression and metastasis, is frequently overexpressed in various cancers. However, its specific role in epidermal growth factor receptor (EGFR)mutant non-small cell lung cancer (NSCLC) remains unclear. This study aimed to investigate the prognostic significance of High mobility group AT-hook 2 (HMGA2), its relationship with EGFR mutations, and its impact on tumor microenvironment (TME) dynamics to identify potential therapeutic targets. Methods: The expression of HMGA2 in different organ tissues and its relevance in NSCLC were examined via the Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Prognostic analysis was conducted via the Kaplan-Meier (KM) plotter database. HMGA2 protein expression across different subgroups was assessed via the (TIMER) and Assistant for Clinical Bioinformatics (ACLBI) databases. Survival analysis was carried out via R (4.2.1). Furthermore, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were performed to investigate potential pathways associated with HMGA2. The correlation between immune infiltration and HMGA2 expression in lung adenocarcinoma (LUAD) was analysed via The Cancer Genome Atlas (TCGA) database. Western blot (WB) analysis was utilized to determine HMGA2 expression in LUAD cell lines. Results: These results indicated that HMGA2 was upregulated in various malignant tumors, including LUAD and lung squamous cell carcinoma (LUSC), and is correlated with poor prognosis in LUAD patients. In LUAD, HMGA2 expression was associated with EGFR mutations, with elevated expression in EGFRmutant (EGFRmut) LUAD linked to a worse prognosis. Additionally, HMGA2 was sensitive to multiple chemotherapy drugs and was involved in various cancer-related signalling pathways, such as extracellular matrix (ECM) receptor interactions, nitrogen metabolism, arrhythmogenic right ventricular cardiomyopathy, and complement and coagulation cascades. Analysis of immune infiltration suggested that HMGA2 was linked to the infiltration of diverse immune cells. Conclusions: In conclusion, HMGA2 expression is positively correlated with the EGFR mutation status, suggesting its potential as a diagnostic and prognostic marker for LUAD.