Fig. 2

Molecular mechanisms of circRNAs related to GC metastasis. A. Roles of circRNAs in signaling pathways associated with EMT. I. The circRNA circTHBS1 increases the INHBA level via adsorbing miR-204-5p in a sponge form, and stabilizes the INHBA mRNA via sequestering HuR protein, leading to the activation of the TGF-β pathway. II. CircAXIN1-encoded a novel protein, AXIN1-295aa interacts with APC to activate the canonical Wnt/β-catenin signaling pathway. III. The circRNA circAKT3 activates the PI3K/AKT signaling by serving as a ceRNA against miR-198 to upregulate PIK3R1. IV. CircTNPO3 competitively binds to IGF2BP3, leading to the destabilization of the MYC mRNA, consequently repressing the expressions of MYC and its target SNAIL. V. The circFNDC3B level is significantly increased in GC and circFNDC3B interacts with IGF2BP3 protein and CD44 mRNA to form a ternary complex, resulting in the upregulation of CD44, which facilitates EMT in GC. VI. The circRNA circ_100876 interacts with miR-665 to relieve the repressive effect on its target YAP1, which is involved in the transcriptional activation of EMT-related genes. B. Roles of circRNAs engaged in angiogenesis. I. CircRanGAP1 is validated to stimulate angiogenesis via modulating the miR-877-3/VEGFA axis. II. CircURI1, a highly expressed circRNA in GC, sequesters the splicing factor, hnRNPM protein in a sequence-dependent manner to modulate alternative splicing of a subset of migration-related genes, such as VEGFA, consequently inhibiting GC metastasis. III. Ebv-circLMP2A promotes angiogenesis through forming a positive feedback loop with HIF1α to improve the VEGFA expression. Under hypoxia, HIF1α up-regulates ebv-circLMP2A, and ebv-circLMP2A interacts with KHSRP to destabilize the VHL mRNA, resulting in VHL down-regulation and HIF1α accumulation. C. Exosomal circRNA in GC. The circRNA circSHKBP1 promotes GC progression via the miR-582-3p/HuR/VEGF axis, and sequestering HSP90 to suppress STUB1-mediated HSP90 ubiquitination. Additionally, increased exosomal circSHKBP1 could facilitate co-cultured cell growth. D. Other pivotal pathways or targets involved in GC metastasis. I. The circRNA circMRPS35 inhibits GC tumorigenesis through the recruitment of histone acetyltransferase KAT7 to the promoters of FOXO1/3a genes, activating the FOXO1/3a transcription, consequently triggering the FOXO1/3a pathway. II. The circRNA circMAPK1 exerted an anti-tumor effect on GC invasion via generating a 109aa protein forming as a molecular sponge for MEK1, thus inhibiting the phosphorylation of MAPK1 and eventually leading to the inactivation of the MAPK pathway. III. The ciRNA circAGO2 interacts with HuR protein to promote its activation and enrichment on the 3’ UTR of HuR targets, resulting in repressing the AGO2/miRNA-mediated gene silencing involved in cancer progression. IV. The circRNA circHuR sequesters CNBP from the HuR’s promoter, leading to the repressions of HuR and GC progression