MFAP2 upregulation promotes ESCC metastasis via FAK-AKT signaling pathway.

Metastasis is the leading cause of mortality from esophageal squamous cell carcinoma (ESCC). By the time of diagnosis, most ESCC tumors have already invaded the lymph nodes or distant organs; however, it has been challenging to identify and confirm genes with a crucial role in ESCC metastasis. The microfibrillar-associated protein 2 (MFAP2) is upregulated in human ESCC, and its expression level was positively associated with poor overall and disease-free survival. Consistently, upregulation of MFAP2 promoted the metastasis and invasion of ESCC cells in vitro and in vivo. Conversely, these processes were reduced by MFAP2 knockdown. Mechanistically, MFAP2 was shown to bind to the FERM domain of focal adhesion kinase (FAK) and to alleviate FAK intramolecular inhibition, resulting in the enhanced binding affinity between FAK and integrin beta 4 (ITGB4) and activation of the FAK-AKT signaling pathway. Treatment of ESCC cells with the FAK inhibitor PND-1186 reduced MFAP2, induced the activation of the FAK-AKT pathway in vitro, and suppressed lung metastasis in a mouse model of ESCC. These findings support a major role for MFAP2 in promoting ESCC metastasis, in part via the activation of FAK-AKT signaling, and highlight the potential of MFAP2 as a promising therapeutic target for ESCC.