Interleukin-33-nuclear factor-κB-CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by...

Esophageal cancer is currently one of the most fatal cancers. However, there is no effective treatment. Increasing evidence suggests that interleukin (IL)-33 has a significant role in tumor progression and metastasis. Currently, the underlying cellular and molecular mechanism of IL-33 in promoting esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we investigated whether IL-33 could induce the epithelial-mesenchymal transition (EMT) in ESCC. Interleukin-33 expression was examined in ESCC and corresponding adjacent normal tissues by immunohistochemistry and quantitative real-time PCR experiments. Elevated IL-33 levels were observed in ESCC tissues. Further in vitro experiments were undertaken to elucidate the effect of IL-33 on migration and invasion in KYSE-450 and Eca-109 esophageal cancer cells. Knockdown of IL-33 decreased the metastasis and invasion capacity in esophageal cancer cells, whereas IL-33 overexpression showed the opposite effect. We then screened CCL2 which is a downstream molecule of IL-33, and proved that IL-33 could promote tumor development and metastasis by recruiting regulatory T cells (Tregs) through CCL2, and IL-33 regulated the expression of CCL2 through transforming growth factor-β in Treg cells. Knockdown of IL-33 decreased the development of human ESCC xenografts in BALB/c nude mice. Collectively, we found that the IL-33/nuclear factor-κB/CCL2 pathway played an essential role in human ESCC progress. Hence, IL-33 should be considered as an effective therapy target for ESCC.