Cancer stemness-modulating circular RNAs in colorectal tumorigenesis: target proteins and regulatory mechanisms

Cancer stem cells (CSCs), a small subpopulation of tumor cells with well-defined traits, play critical roles in tumorigenesis. Circular RNAs (circRNAs) have emerged as important regulators of cancer stemness and tumorigenesis. Applying stringent selection criteria, this review aims to systematically evaluate the literature to functionally define a distinct class of cancer stemness-modulating circRNAs (CSM-circRNAs) in colorectal cancer (CRC). In CRC, fourteen dysregulated CSM-circRNAs are identified all of which were validated in spheroid formation assays and expression of multiple stemness markers. All CSM-circRNAs, except circFNDC3B, are up-regulated in CRC, and many (7/14) are selectively pan-cancer dysregulated. Most (9/14) act through miRNA sponging, while the remainder (5/14) function via interactions with RNA-binding proteins. CSM-circRNA dysregulation affects key CSC traits, confirming their role in modulating cancer stemness. Among the fifteen CSM-circRNA-regulated proteins identified, ten are (post-)transcriptional or (post-)translational regulators, and five are signaling or structural proteins. The CRC CSM-circRNA-regulated proteins are dysregulated across multiple cancer types besides CRC, influencing key biochemical and signaling pathways. We propose that CSM-circRNAs constitute a novel class of post-transcriptional regulators that broadly activate cancer stem cells and driving malignant progression, highlighting their diagnostic and therapeutic potentials. It is anticipated that CSM-circRNAs in other cancers, and other functional circRNA categories across diseases, will be similarly categorized, providing systematic frameworks for organizing the rapidly expanding circRNA literature.