IL-37 inhibits invasion and metastasis in non-small cell lung cancer by suppressing the IL-6/STAT3 signaling pathway

Abstract

Background: IL-37 has been identified as a fundamental inhibitor of inflammatory and immunity responses. It plays a crucial protective role in several cancers, but its anti-tumor activity and the potential regulatory mechanism of IL-37 in non-small cell lung cancer (NSCLC) is largely unclear. Methods: Enzyme-linked immunosorbent assay was used to detect plasma IL-37 expression in NSCLC patients and healthy controls. The NSCLC cell line A549 was cultured with recombinant human IL-37 or recombinant human IL-6 protein. A549 invasion and metastasis were detected using Transwell invasion and scratch wound healing assays, respectively. Protein expression of STAT3, pSTAT3, E-cadherin, vimentin, and N-cadherin were detected using Western blotting, and messenger RNA expression of STAT3, E-cadherin, vimentin, and N-cadherin was assessed in each group using real time PCR. Results: IL-37 plasma expression was decreased in NSCLC patients, and the downregulation of IL-37 was correlated with tumor stage. In vitro, IL-37 inhibited invasion and migration in A549 cells, while IL-6 promoted invasion and migration in A549 cells. pSTAT3, vimentin, and N-cadherin expression was increased. E-cadherin expression was lower in the IL-6 group than in the control group; however, the opposite pattern was observed in the IL-37 + IL-6 group. Conclusion: Our results showed that IL-37 plays an inhibitory role in NSCLC progression, possibly by suppressing STAT3 activation and decreasing epithelial-to-mesenchymal transition by inhibiting IL-6 expression. IL-37 could serve as a potential novel tumor suppressor in NSCLC.