Transcriptomic analysis reveals lung cancer and subtype-specific alternative splicing biomarkers regulated by RNA-binding proteins.

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, and the complex molecular mechanisms underlying its development, particularly the role of alternative splicing (AS) in different subtypes, remain poorly understood. In this study, we performed RNA sequencing of 178 lung cancer patients and conducted a comprehensive analysis of the transcriptomic landscape with a focus on AS. We identified robust lung cancer- and subtype-specific AS biomarkers that were consistently effective in both tissue samples and cancer cell lines. Notably, several of these biomarkers also serve as critical regulators in lung cancer progression. Our regulatory network analysis, with a focus on RNA-binding proteins, revealed QKI and SR proteins as key splicing factors. Specifically, QKI was found to modulate the splicing of PLEKHA1 exon 15, a cancer-specific AS biomarker, while SRSF1 regulated the splicing of MKNK2 exon 14, a subtype-specific AS biomarker. Our study provides valuable insights into key AS events and their regulatory mechanisms in lung cancer, paving the way for potential therapeutic targets.