Comprehensive pan-cancer analysis of LAMA3: implications for prognosis and immunotherapy.

Abstract

Objectives: Laminin subunit alpha 3 (LAMA3) has been implicated in various cellular processes relevant to cancer progression, including cell proliferation, migration, and adhesion. In this study, we explored the expression, prognostic significance, and functional role of LAMA3 across multiple cancer types.

Methodology: The in silico analyses involve using various bioinformatics tools and databases, such as The Cancer Genome Atlas (TCGA), TIMER2.0, GEPIA2, UALCAN, Kaplan-Meier (KM) plotter, GENT2, Human Protein Atlas (HPA), OncoDB, Gene Set Cancer Analysis (GSCA), and TISIDB. The in vitro analyses include cell culture, gene knockdown, and assays for cell proliferation, colony formation, and wound healing.

Results: Pan-cancer analysis revealed significant variations in LAMA3 expression, with upregulation observed in cancers such as pancreatic adenocarcinoma (PAAD) and stomach adenocarcinoma (STAD), and downregulation in breast cancer (BRCA) and colon adenocarcinoma (COAD). Prognostic analyses indicated high LAMA3 expression correlated with poor overall survival (OS) in PAAD and STAD, whereas low expression was associated with adverse outcomes in BRCA. Validation analysis confirmed differential expression and localized LAMA3 primarily to the endoplasmic reticulum. Analysis of clinical features in BRCA, PAAD, and STAD showed consistent expression trends across different stages, races, and age groups. Additionally, mutational and copy number variations (CNVs) analyses revealed prevalent heterozygous amplifications and deletions in LAMA3 across BRCA, PAAD, and STAD. Promoter methylation was inversely correlated with LAMA3 expression in BRCA, PAAD, and STAD, although survival outcomes were unaffected. Protein-protein interaction (PPI) and gene enrichment analyses indicated LAMA3's involvement in ECM-receptor interactions and PI3K-Akt signaling, pathways critical in cancer. Finally, functional assays following LAMA3 knockdown in HT-29 cells demonstrated reduced cell proliferation, colony formation, and wound healing, implicating LAMA3 in tumor growth and metastasis.

Conclusion: Overall, these findings suggest that LAMA3 plays a multifaceted role in tumorigenesis and holds potential as a prognostic biomarker and therapeutic target in multiple cancers.