Guoyang He: Department of Pathology, Xinxiang Medical University, Xinxiang, China. ORCID
Wei Li: School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China.
Wenli Zhao: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Hui Men: Department of Pathology, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China.
Qingqing Chen: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Jinlong Hu: Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Jingyu Zhang: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Huifang Zhu: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Wenxin Wang: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Meijing Deng: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Zishan Xu: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Gaoxiang Wang: Department of Colorectal and Anal Surgery, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Lin Zhou: Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xinlai Qian: Department of Pathology, Xinxiang Medical University, Xinxiang, China.
Li Liang: Department of Pathology, Southern Medical University, Guangzhou, China.
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). Formin-like 2 promotes EGFL6 paracrine signaling by exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. Epidermal growth factor-like protein 6 binds to the N-terminus of CKAP4 to promote the migration of HUVECs by activating the 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 could be a candidate therapeutic target for CRC treatment.
