Background: Angiogenesis plays an important role in the metastasis of cancers. However, the mechanisms whereby circular RNAs (circRNAs) regulate angiogenesis and affect cancer metastasis are still unclear.

Methods: We used gene set variation and Spearman’s correlation analyses to identify novel angiogenesis-related circRNAs, including circFAM169A. The Kyoto Encyclopedia of Genes and Genomes and Gene Ontology were used to assess the potential biological function of circFAM169A. A quantitative reverse transcription–PCR (qRT-PCR) analysis of 20 pairs of colorectal cancer (CRC) samples was performed to detect the expression level of circFAM169A. Transwell assays, tube formation assays, and nude mouse metastatic tumor models were used to study the function of circFAM169A in CRC. qRT-PCR, dual-luciferase reporter gene assay, RNA antisense purification assay, and Western blot were performed to analyze the competing endogenous RNA mechanism of circFAM169A in promoting CRC angiogenesis.

Results: circFAM169A was highly correlated with the hallmark of angiogenesis in CRC patients. It was up-regulated in liver metastasized CRC patients. circFAM169A overexpression promoted the angiogenesis, migration, and invasion of CRC cells while its down-regulation had the opposite effects. In vivo mouse models further highlighted the pro-metastatic role of circFAM169A in CRC. More importantly, we discovered that circFAM169A enhances the expression of angiopoietin-2 by binding to miR-518a-5p.