Synaptotagmin 1 Suppresses Colorectal Cancer Metastasis by Inhibiting ERK/MAPK Signaling-Mediated Tumor Cell Pseudopodial Formation and Migration

Simple Summary Colorectal cancer (CRC) is one major cause of cancer mortality worldwide. Emerging evidence shows that synaptotagmin 1 (SYT1) takes roles in a variety of cancers. However, the role of SYT1 in colorectal cancer remains an enigma. Here, we first assess SYT1 expression levels and discover that its expression is downregulated in CRC tissues and CRC cell lines. We further confirm that SYT1 overexpression suppresses CRC metastasis both in vivo and in vitro using mouse CRC xenograft metastasis model and colon cancer cells. The inhibitory effect of SYT1 overexpression on CRC metastasis is associated with reductions of CRC cell pseudopodial formation, migration, and invasion. Mechanistically, SYT1 overexpression inhibits EMT via negatively regulating the ERK/MAPK signaling, thereby resulting in suppression of CRC cell migration and invasion. Our findings provide new insights into CRC development and indicate the potential of SYT1 as a bio marker and potential therapeutic target for CRC.Abstract Although synaptotagmin 1 (SYT1) has been identified participating in a variety of cancers, its role in colorectal cancer (CRC) remains an enigma. This study aimed to demonstrate the effect of SYT1 on CRC metastasis and the underlying mechanism. We first found that SYT1 expressions in CRC tissues were lower than in normal colorectal tissues from the CRC database and collected CRC patients. In addition to this, SYT1 expression was also lower in CRC cell lines than in the normal colorectal cell line. SYT1 expression was downregulated by TGF-beta (an EMT mediator) in CRC cell lines. In vitro, SYT1 overexpression repressed pseudopodial formation and reduced cell migration and invasion of CRC cells. SYT1 overexpression also suppressed CRC metastasis in tumor-bearing nude mice in vivo. Moreover, SYT1 overexpression promoted the dephosphorylation of ERK1/2 and downregulated the expressions of Slug and Vimentin, two proteins tightly associated with EMT in tumor metastasis. In conclusion, SYT1 expression is downregulated in CRC. Overexpression of SYT1 suppresses CRC cell migration, invasion, and metastasis by inhibiting ERK/MAPK signaling-mediated CRC cell pseudopodial formation. The study suggests that SYT1 is a suppressor of CRC and may have the potential to be a therapeutic target for CRC.