Synaptotagmin 7 in Twist-Related Protein 1-Mediated Epithelial-Mesenchymal Transition of Non-Small Cell Lung Cancer

Background: Twist-related protein 1 (TWIST1) plays an essential role in the carcinogenesis and metastasis of NSCLC. Our aims were to identify a novel molecule at the downstream of TWIST1 that mediates metastasis of NSCLC, and to evaluate its potential as a diagnosis and a prognosis marker.   Methods: The functional genes associated with invasion and metastasis at the downstream of TWIST1 were obtained by microarray gene expression analyses in NSCLC cell line. The expression levels of Synaptotagmin 7 (SYT7) in a cohort of patients with NSCLC (n=154) were examined by immunohistochemistry staining, and assessed by Kaplan-Meier survival analysis and Cox regression analysis. The effects of SYT7 on tumorgenesis and metastasis of NSCLC were measured in vitro and in vivo.   Findings: We first discovered that SYT7 is significantly altered by TWIST1 expression in microarray gene expression analyses. We further confirmed that SYT7 protein was significantly higher in NSCLC tissues than that in the adjacent normal lung tissues, and higher SYT7 protein expression was associated with poor survival of NSCLC patients. Functional experiments indicated that SYT7 promotes proliferation, invasion and metastasis, and inhibits cell apoptosis of NSCLC cells in vitro and in vivo. We demonstrated that knocking down SYT7 increases expression of E-cadherin and decreases the level of N-cadherin and Vimentin of cultured cells, indicating an involvement of EMT by SYT7.   Interpretation: Our data indicate that SYT7 is an important promoter for EMT and tumor progression in NSCLC.   Funding: This project was supported by grants from the Major Scientific and Technological Innovation Project of Shandong Province (2018CXGC1212), Science and Technology Foundation of Shandong Province (2014GSF118084, 2016GSF121043), Medical and Health Technology Innovation Plan of Jinan City (201805002) and the National Natural Science Foundation of China (81372333). Declaration of Interest: No potential conflicts of interest were disclosed. Ethical Approval: This study was conducted with the approval of the ethical committees of Qilu Hospital of Shandong University (Jinan, China).