SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

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.

GDF15 deficiency hinders human trophoblast invasion to mediate pregnancy loss through downregulating Smad1/5 phosphorylation

“…In addition, previous research has found a link between GDF15 and invasion in other cancers. 20 , 21 , 22 , 23 , 24 …”

Macrophages as a Source and Target of GDF-15

“…Elevated GDF-15 has been strongly associated with metastasis in prostate, esophageal, hepatocellular, colorectal, pancreatic, gastric, and endometrial cancers [151]. Esophageal, breast, and colon cancer models show that GDF-15 correlates with the loss of E-cadherin and that the inhibition of GDF-15 expression decreases cell migration and invasion ability [70,152,153]. In contrast, in A549 lung cancer cells, overexpression of GDF-15 reduces cell growth and migration and decreases the spread of lung and bone metastases [154].…”

KLF4 suppresses the proliferation of perihilar cholangiocarcinoma by negatively regulating GDF15 and phosphorylating AKT

“…Over the course of the past few years, it has been shown to participate in carcinogenesis and tumor progression. Previous studies have indicated that GDF15 expression is elevated in certain types of tumor, including non-small cell lung cancer (16), cervical cancer (17), liver cancer (18), head and neck cancer (19), esophageal cancer (20), and so on (21)(22)(23)(24). However, certain studies have suggested that GDF15 may have a tumor-suppressive activity in various types of cancer cells, or at different stages of tumor growth (25).…”