Circular RNA profiling identifies circ102049 as a key regulator of colorectal liver metastasis

Here, we identify circ102049 as a regulator of metastatic colorectal cancer (CRC). High circ102049 levels were correlated with poor clinical outcomes in patients with CRC and promoted liver metastasis in an FRAS1‐dependent manner. Circ102049 regulated the levels of the FRAS1‐targeting miR‐761 and miR‐192‐3p both directly (acting as a miRNA sponge) and indirectly (modifying the subcellular localization of the RNA binding protein DGCR8). Circular RNA (circRNA) plays an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNA in colorectal liver metastasis have not been fully elucidated. We performed circRNA microarray analysis to screen differentially expressed circRNA in the pathology of colorectal liver metastasis. Quantitative real‐time PCR was used to detect the expression of hsa_circ_102049 (circ102049) in colorectal cancer (CRC) samples. CRC cells were transfected with circ102049 overexpression vector or small interfering (si)RNA to assess the effects of circ102049 in vitro. Bioinformatics analysis, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull‐down and luciferase reporter assays were conducted to confirm the relationship of circ102049, miR‐761, miR‐192‐3p and FRAS1. The mechanism by which circ102049 recruits and distributes DGCR8 protein in the cytoplasm was also investigated. We found that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the prognosis of patients with CRC. Circ102049 significantly enhanced the adhesion, migration and invasion abilities of CRC cells, and promoted CRC progression via a micro (mi)R‐761/miR‐192‐3p‐FRAS1‐dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 may also indirectly reduce the levels of mature miR‐761 and miR‐192‐3p in the cytoplasm. In addition, the role of circ102049 in promoting colorectal liver metastasis was confirmed in vivo. Our findings provide new evidence that circ102049 may be a potential prognostic factor in CRC, and that the circ102049‐miR‐761/miR‐192‐3p–FRAS1 axis may be an anti‐metastatic target for CRC patients.