MIIP Inhibits Colorectal Cancer Progression by Modulating Neutrophils Infiltration and Neutrophil Extracellular Trap Formation

ABSTRACT

Neutrophil extracellular traps (NETs) contribute to colorectal cancer (CRC) progression, but the underlying regulatory mechanism remains unknown. This study explored how migration and invasion inhibitory protein (MIIP) influences CRC progression by regulating tumor‐associated neutrophils (TANs) infiltration and NETs formation. On the basis of bioinformatics analysis and clinical CRC samples, we observed that a high density of neutrophils and a high abundance of NETs were correlated with low MIIP expression in CRC tissue as well as distant metastasis and poor prognosis. In vitro co‐culture assays revealed that conditioned medium from CRC cells with downregulated MIIP expression recruited neutrophils to form NETs and that NETs further enhanced the migratory and invasive abilities of CRC cells. Mechanistically, the results of this study demonstrated that MIIP directly bound to Protein Kinase R, which inhibited the Nuclear Factor kappa‐B pathway and Interleukin ‐ 8 expression and accordingly suppressed TANs infiltration and NETs formation. In addition, preliminary results from an intrasplenic mouse model of CRC liver metastasis suggested the potential therapeutic significance of Deoxyribonuclease I (DNase I, a NET inhibitor), and MIIP augmented the inhibition of CRC metastasis by DNase I. This study revealed that MIIP is a regulator of CRC cell‐neutrophil crosstalk and indicated that NETs are potential therapeutic targets in CRC.