Fig. 5

Six general mechanisms underlying the functions of circRNAs in colorectal cancer. a | Function as miRNA sponges or decoys. For example, circCSE1L and circHOXA9 protect their homologous mRNAs from miRNA-mediated degradation by inhibiting miRNA activity. A few circRNAs may also indirectly activate or inactivate vital signaling pathways by suppressing miRNAs. b | Function as protein sponges or decoys. In the cytoplasm, circPTK2 physically interacts with the vimentin protein at phosphorylation sites Ser38, Ser55 and Ser82, protecting vimentin from phosphorylation by PKA, CDK1 or PLK. c | Enhances protein function. As illustrated in the figure, circNSUN2 interacts with IGF2BP2 and HMGA2 mRNA and forms a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex, increasing the stability of the HMGA2 mRNA. d | Function as a protein scaffold. In response to energy stress, circACC1 binds the regulatory β and γ subunits of AMPK and promotes the assembly, stabilization, and activity of the AMPK holoenzyme. e | Function as protein recruiters. In the nucleus, circLONP2 recruits DGCR8 and the Drosha complex to the primary miR-17 (pri-miR-17) in a DDX1-dependent manner and facilitates the maturation and processing of pri-miR-17. Then, the upregulated mature miR-17-5p not only promotes the metastasis of highly metastatic CRC (HM-CRC) cells by inhibiting PTEN translation but is also assembled into exosomes and internalized by low metastatic CRC (LM-CRC) cells to enhance their aggressiveness. Another example is circCTIC1, which interacts with the NURF complex through BPTF, recruits the NURF complex to the c-Myc promoter and finally drives the transcriptional initiation of the c-Myc gene. f | Function as translation templates. circPPP1R12A carries a short 216-nt open reading frame (ORF) and encodes a functional protein (named circPPP1R12A-73aa). Another circRNA with peptide-coding capacity is circLgr4