Targeting BUB1B-driven cancer stemness in lung adenocarcinoma: a novel therapeutic strategy via PI3K/AKT pathway...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Tumor stemness is a critical factor in lung adenocarcinoma (LUAD) progression and therapeutic resistance.
• The molecular underpinnings and clinical relevance of stemness in LUAD require further elucidation.
• This study investigates the tumor stemness index (mRNAsi) to uncover potential therapeutic targets in LUAD.

Purpose of the Study:

• To evaluate the role and clinical significance of the tumor stemness index (mRNAsi) in lung adenocarcinoma (LUAD).
• To identify key regulatory genes associated with stemness in LUAD.
• To explore the relationship between stemness, the tumor immune microenvironment (TIME), and clinical features in LUAD.

Main Methods:

• Analysis of transcriptomic data from TCGA and PCBC datasets to assess mRNAsi in LUAD.
• Weighted gene co-expression network analysis (WGCNA) to identify stemness-related genes.
• Prioritization of core regulatory genes using LASSO, SVM-RFE, and random forest with Boruta (RFB), followed by independent dataset validation.

Main Results:

• Elevated mRNAsi correlated with aggressive clinicopathological features and an immune-cold TIME (Immune_L).
• Budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) was identified as a central regulator of LUAD stemness.
• BUB1B promotes proliferation, migration, invasion, and stemness phenotypes by activating the Ca2+/PI3K/AKT signaling axis.

Conclusions:

• BUB1B is a pivotal regulator of LUAD stemness and malignancy, connecting mRNAsi with clinical, immune, and genomic aspects.
• BUB1B shows promise as a diagnostic, prognostic, and therapeutic biomarker for LUAD.
• Multicenter validation is recommended to confirm the clinical utility of BUB1B in LUAD.