<scp>FMNL2</scp> promotes angiogenesis and metastasis of colorectal cancer by regulating <scp>EGFL6</scp> / <scp>CKAP4</scp> / <scp>ERK</scp> axis

Increasing evidence indicates that angiogenesis plays a pivotal role in tumor progression. Formin-like 2 (FMNL2) is well-known for promoting metastasis; however, the molecular mechanisms by which FMNL2 promotes angiogenesis in colorectal cancer (CRC) remain unclear. Here, we found that FMNL2 promotes angiogenesis and metastasis of CRC in vitro and in vivo. The GDB/FH3 domain of FMNL2 directly interacts with epidermal growth factor-like protein 6 (EGFL6). FMNL2 promotes EGFL6 paracrine signaling via exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. EGFL6 binds to the N-terminus of CKAP4 to promote the migration of human umbilical vein endothelial cells (HUVECs) by activating ERK/MMP pathway. These findings suggest that FMNL2 promotes the migration of HUVECs and enhances angiogenesis and tumorigenesis in CRC by regulating the EGFL6/CKAP4/ERK axis. Therefore, the EGFL6/CKAP4/ERK axis may be a candidate therapeutic target for CRC treatment.