SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer.

Gang Dong,Xiaoquan Huang,Shiyao Chen,Chouwen Zhu,Siyu Jiang,Lili Ma,Liyuan Ni

doi:10.3389/fonc.2020.564785

Abstract

Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood.Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings.Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs.Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

Highlights

esophageal cancer (EC) is a common malignant tumor with a worldwide prevalence [1]
The results of our study indicated the significance of the Growth differentiation factor 15 (GDF15)/sterol regulatory element-binding protein cleavage-activating protein (SCAP)/SREBF2 axis for EC metastasis and suggested that this pathway could be therapeutically targeted
Using the gene expression TCGA database, we observed that GDF15 expression was higher in EC compared to adjacent normal tissue (Figure 1A)

Summary

Introduction

EC is a common malignant tumor with a worldwide prevalence [1]. An estimated 246,000 new cases were diagnosed in China in 2015, with approximately 188,000 dying from the disease [2]. It is important to identify the molecular mechanisms underlying metastasis of EC to aid in the development of new treatment strategies for EC patients. Inflammation, obesity, cardiovascular diseases, and tumors have been shown to induce abnormal expression of GDF15 [4, 5]. GDF15 has served as a potential biomarker for patients with EC [10]. The biological function of GDF15 in EC remains poorly understood. Previous reports regarding the role of GDF15 in the invasion and metastasis of EC are rare, with the underlying mechanism yet to be deciphered. GDF15 is a potential biomarker for patients with esophageal cancer (EC). The mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood

Methods

Results

Conclusion