Long non-coding RNAs as regulators, biomarkers, and therapeutic targets in colorectal cancer

Abstract Colorectal cancer (CRC) is the third most spread cancer globally, commonly arising from activation of the Wnt/β-catenin signaling pathway and microsatellite instability (MSI). Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides and serve as crucial regulators in CRC progression. Depending on their subcellular localization, lncRNAs can be nuclear (e.g., MALAT1), cytoplasmic (e.g., H19), or exosomal, and are genomically classified as sense, antisense, divergent, intergenic, and intronic. They modify gene expression through cis- and trans-regulation functions, regulate mRNA stability through RNA-binding proteins, and function as competitive endogenous RNAs (ceRNAs). LncRNAs control the function of proteins using scaffolding or decoy mechanisms. While exosomal RPPH1 and CAF-derived H19 enhance metastasis by activating β-catenin signaling, oncogenic lncRNAs like HOTAIR and CCAT1-L promote the growth of colorectal cancer. New RNA-based therapies, including RNA interference (RNAi), antisense oligonucleotides (ASOs), and CRISPR technologies (CRISPRi, CRISPR-Cas13, and CRISPR/Cas9), show promising methods for downregulating oncogenic miRNAs (miR-21), restoring tumor-suppressive miRNAs (miR-145), and suppressing carcinogenic lncRNAs like EPIC1, CCAT1, and CCAT2.