Synaptotagmin 7 in twist-related protein 1-mediated epithelial - Mesenchymal transition of non-small cell lung cancer

Xiao Liu; Chunyu Li; Yie Yang; Xiaoxia Liu; Rui Li; Mengyu Zhang; Yunhong Yin; Yiqing Qu

doi:10.1016/j.ebiom.2019.07.071

Synaptotagmin 7 in twist-related protein 1-mediated epithelial - Mesenchymal transition of non-small cell lung cancer

EBioMedicine. 2019 Aug:46:42-53. doi: 10.1016/j.ebiom.2019.07.071. Epub 2019 Aug 6.

Authors

Xiao Liu¹, Chunyu Li², Yie Yang³, Xiaoxia Liu¹, Rui Li¹, Mengyu Zhang¹, Yunhong Yin¹, Yiqing Qu⁴

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China.
² Department of Respiratory Medicine, First Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
³ Department of Clinical Laboratory, Qianfoshan Hospital of Shandong Province, Jinan 250012, China.
⁴ Department of Respiratory and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: quyiqing@sdu.edu.cn.

Abstract

Background: Twist-related protein 1 (TWIST1) plays an essential role in the carcinogenesis and metastasis of NSCLC. Our aims were to identify the molecule at the downstream of TWIST1 and to evaluate its potential as a diagnostic and a prognostic marker in NSCLC.

Methods: The functional genes at the downstream of TWIST1 were obtained via microarray gene expression analyses in the NSCLC cell line. The expression levels of synaptotagmin 7 (SYT7) in a cohort of patients with NSCLC (n = 154) were examined using immunohistochemistry staining and assessed by Kaplan-Meier survival analysis and Cox regression analysis. The effects of SYT7 on the tumorigenesis and metastasis of NSCLC were measured in NSCLC cells. In vivo xenograft lung cancer models were used to study the tumorigenesis role of SYT7.

Findings: We discovered that SYT7 is significantly altered by TWIST1 expression. We further confirmed that SYT7 protein was significantly higher in NSCLC than that in the adjacent normal lung tissue, and higher SYT7 expression was associated with poor survival of NSCLC patients. The protein level of SYT7 was positively correlated with TWIST1 in NSCLC tissue. Functional experiments indicated that SYT7 promoted proliferation, invasion, and metastasis and inhibited cell apoptosis of NSCLC cells in vitro. In vivo experiments showed that shSYT7 inhibited the xenograft tumor growth of NSCLC cells. Knocking down of SYT7 increased the expression of E-cadherin and decreased the level of N-cadherin and Vimentin in cultured cells.

Interpretation: Our data indicate that SYT7 is an important promoter for EMT and tumor progression in NSCLC. FUND: 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).

Keywords: Metastasis; NSCLC; SYT7; TWIST1; Tumorigenesis.

MeSH terms

Animals
Biomarkers, Tumor
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism*
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Computational Biology / methods
Disease Models, Animal
Epithelial-Mesenchymal Transition / genetics*
Female
Gene Expression Profiling
Gene Knockdown Techniques
Humans
Immunohistochemistry
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism*
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Mice
Prognosis
Synaptotagmins / genetics*
Synaptotagmins / metabolism
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism*
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
Twist-Related Protein 1
Synaptotagmins