Identification of RNA binding proteins targeting TP53, RB1 and PTEN in colorectal cancer as potential biomarkers for diagnosis, drug resistance, sensitivity and prognosis
TL;DR
Twenty-two RBPs were identified as candidate binding-associated regulators of key tumor suppressors and seven RBPs involved in prominent pathways were identified as candidate prognostic biomarkers requiring further validation in independent cohorts before any clinical application can be considered in CRC, although these findings remain exploratory and require further functional validation.
Abstract
Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy with high incidence and mortality. Dysregulated RNA-binding proteins (RBPs) have been implicated in various cancers, yet their role in regulating tumor suppressors in CRC is underexplored. This study analyzed TCGA gene expression data to identify prognostic markers and used CLIP-seq data to uncover RBPs putatively binding to TP53, RB1, and PTEN. Functional enrichment via Gene Ontology (GO) and MSigDB Hallmark pathways suggested involvement in mRNA processing, Myc Targets V1, and Unfolded Protein Response. Univariate Cox regression analyses identified high expression of NOP56, EIF4A3, and IGF2BP1 as associated with poor survival, while high RBM47 expression was linked to improved prognosis; these findings were validated using Kaplan–Meier survival curves. However, multivariate Cox regression analysis was not performed, and independent prognostic validation is required. ROC analysis further indicated that several RBPs could distinguish tumor from normal tissues. Importantly, these AUC values were derived from the TCGA discovery dataset and require independent external validation before any diagnostic application can be considered. Drug sensitivity analyses using GDSC and CCLE datasets revealed exploratory and unadjusted associations between elevated NOP56, FBL, and FUS expression and increased sensitivity to Irinotecan, Nilotinib, and Raf265. A multi-cohort integrated analysis and qRT-PCR confirmed upregulation of selected RBPs in CRC tissues and cell lines. Importantly, these CLIP-seq interactions reflect physical binding potential rather than direct functional regulation of target gene expression. Overall, 22 RBPs were identified as candidate binding-associated regulators of key tumor suppressors, and seven RBPs involved in prominent pathways were identified as candidate prognostic biomarkers requiring further validation in independent cohorts before any clinical application can be considered in CRC, although these findings remain exploratory and require further functional validation.