Abstract

BackgroundTumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) was initially considered an immunity guard; however, its function remains controversial. Besides immune cells, lung and colon cancer cells have also been reported to express TRAIL, which can promote tumor invasion and metastasis. However, the biological function and underlying mechanism of action of TRAIL in esophageal squamous cell carcinoma (ESCC) remain poorly elucidated.MethodsThe ESCC cells stemness, migration, and proliferation ability was assessed by sphere formation, Transwell, and CCK8 assay. The stemness- and epithelial-mesenchymal transition (EMT)- related genes expression levels were analyzed by Western blot and RT-qPCR. The signal activation was conducted by Western blot. The xenograft mouse experiments and lung metastasis model were performed to confirm our findings in vitro.ResultsHerein, we found that TRAIL is a negative predictor in patients with ESCC. To further investigate the biological function of TRAIL, we established TRAIL knockdown and overexpression ESCC cell lines and found that TRAIL induced EMT and promoted tumor aggressiveness. Furthermore, we demonstrated that TRAIL- overexpressing cells upregulated PD-L1 expression, which was dependent on the p-ERK/STAT3 signaling pathway. We obtained similar results when using recombinant human TRAIL. Finally, we validated the biological role and mechanism of action of TRAIL in vivo.ConclusionsThese findings demonstrate that TRAIL promotes ESCC progression by enhancing PD-L1 expression, which induces EMT. This may explain the failure of TRAIL preclinical trials.

Highlights

  • Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a member of tumor necrosis factor superfamily (TNFSF) and is encoded by TNFSF10

  • We found that Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) was a poor predictor in patients with esophageal squamous cell carcinoma (ESCC)

  • It is evident that TRAIL can promote ESCC progression by influencing epithelial-mesenchymal transition (EMT), TRAIL has the potential to act as a key molecule to target EMT and inhibit ESCC progression in the future

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Summary

Introduction

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a member of tumor necrosis factor superfamily (TNFSF) and is encoded by TNFSF10. TRAIL was identified with a diversity of functions in the tumor microenvironment. TRAIL induces tumor cells apoptosis via binding to its receptors DR4/5 [7, 8]. Tumor cells could recruit M2 by expressing TRAIL, remodeling the tumor microenvironment and promoting tumor progression [9]. Tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) was initially considered an immunity guard; its function remains controversial. Lung and colon cancer cells have been reported to express TRAIL, which can promote tumor invasion and metastasis. The biological function and underlying mechanism of action of TRAIL in esophageal squamous cell carcinoma (ESCC) remain poorly elucidated

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