Macrophages promote growth, migration and epithelial-mesenchymal transition of renal cell carcinoma by regulating GSDMD/IL-1β axis.

BACKGROUND

Macrophages are highly enriched in renal cell carcinoma, and the inflammatory cytokines secreted by macrophages are remarkably associated with the survival rate of renal cell carcinoma. However, the relationship between gasdermin D (GSDMD) expression driven by macrophage and the invasion of renal cell carcinoma is not clear.

METHODS

The Caki-2 and 786-O cells were co-cultured with monocytes cells (THP-1) derived macrophages, then the bio function changes of Caki-2 and 786-O cells and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of IL-1β in Caki-2 and 786-O cells and macrophage interaction were investigated. Then, the animal model was used to confirm the role of communication of GSDMD with renal cell carcinoma in the tumor microenvironment.

RESULTS

CD68 and GSDMD were overexpressed in human renal cell carcinoma. GSDMD contributed to the secretion of IL‑1β in macrophages and was associated with the proliferation rate of renal cell carcinoma cells. Furthermore, silencing GSDMD elicited renal cell carcinoma cells motility through epithelial-mesenchymal transition change. The in vivo study confirmed that GSDMD promoted tumor progression and GSDMD knockout impaired renal cell carcinoma growth and metastases. Finally, the interactions between macrophages and renal cell carcinoma cells promoted renal cell carcinoma proliferation and metastasis, possibly mediated by IL-1β.

CONCLUSION

To our knowledge, this study showed that the GSDMD expressed by macrophages contributed to renal cell carcinoma cell growth, metastases, and epithelial-mesenchymal transition through regulating GSDMD/IL-1β axis and may be a novel therapeutic target and a potential biomarker for treating and diagnosing renal cell carcinoma.