Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer

Background: interleukin-37 (il-37),a newly identified member of the il-1 family,has been known to play an immunosuppressive role in a variety of inflammatory disorders,but whether it participates in the regulation of pathogenesis of non-small cell lung cancer (nsclc) has not been investigated. methods: real-time polymerase chain reaction (pcr),western blotting,and immunohistochemical staining were employed to detect il-37 expression in nsclc tissues and corresponding adjacent tissues. the correlations between il-37 expression and clinicopathological characteristics,prognosis were analyzed. stable clone with overexpression of il-37 was generated in h1299 cell lines. cell growth,cell cycle and cell apoptosis assays were carried out for detecting proliferation and apoptosis of h1299 cells. the effects of il-37 on nsclc progression in vivo was performed in a xenografted lung tumor model in nude mice. the concentrations of il-37 and vegf in the s growth medium supernatants were quantified by elisa. the antiangiogenic effect of il-37 on huvec was measured by tube formation assay. results: il-37 mrna and protein expressions were significantly decreased in nsclc tissues,and decreased intratumoral il-37 expression was significantly associated with tumor state,tnm stage and poor prognosis in nsclc patients. in addition,intratumoral il-37 expression was an independent prognostic factors for overall survival (hazard ratio=2.047; p=0.011). overexpression of il-37 exerted no direct effect on cell proliferation and apoptosis of h1299 lung cancer cells in vitro,but significantly inhibited tumor growth in a h1299 xenograft model in vivo. furthermore,there was no significant change in immune cell infiltration in il-37 over-expressing tumors; instead,we found decreased microvessel density (mvd) and vegf levels in il-37-expressing tumors. additional studies showed il-37 could directly inhibit huvec cells growth and capillary structure formation. finally,we found that decreased il-37 expression was associated with high mvd in nsclc patients. conclusions: our findings demonstrate a protective role for il-37 in lung cancer development,possibly through inhibiting tumor angiogenesis. il-37 could serve as a promising therapeutic target for nsclc. © 2016 ge et al.