LncRNA LINC00941 Links Oncogenic KRAS Signaling to Aggressiveness and Chemoresistance in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, driven largely by oncogenic KRAS, yet effective targeted therapies remain unavailable. Long noncoding RNAs (lncRNAs) are emerging as key regulators of tumor biology, but their role in KRAS-driven PDAC is not well defined. To address this gap, we integrated RNA sequencing, exome, and clinical data from The Cancer Genome Atlas (TCGA) and identified 49 long intergenic noncoding RNAs (lincRNAs) differentially expressed according to KRAS status. Among the ten most abundant, LINC00941 and AC006262.5 showed the strongest differential expression in an independent PDAC cohort from the International Cancer Genome Consortium (ICGC). Experimental validation in KRAS-mutant PDAC cell lines and isogenic pancreatic epithelial models confirmed KRAS-dependent regulation of LINC00941, which was consistently upregulated in patient tumors and correlated with poor prognosis in both TCGA and ICGC datasets. Single-cell transcriptomic analysis further demonstrated that LINC00941 is enriched in malignant epithelial populations. Functional assays revealed that LINC00941 silencing impaired migration and invasion, reduced DNA repair capacity, and sensitized PDAC cells to gemcitabine, while having little effect on viability. Supporting these findings, co-expression and enrichment analyses linked LINC00941 to pathways regulating cell adhesion, motility, extracellular matrix organization, and DNA repair. Together, these findings demonstrate that oncogenic KRAS reshapes the lncRNA landscape in PDAC and identify LINC00941 as a KRAS-regulated oncogenic lncRNA that promotes aggressiveness and chemoresistance, highlighting its prognostic value and potential as a therapeutic target.