title: Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277, Yantaxi Road, Xi'an, 710061, Shaanxi, China. geguanqun@xjtu.edu.cn.
authors.forename: Guanqun
authors.initials: G
authors.lastname: Ge
authors.affiliation: Department of Neurosurgery, The Ninth Hospital of Xian, Xi'an, 710054, China. aegeanwang@126.com.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, No.15 Changle West Road, Xi'an, Shannxi, 710032, China. moonyue1988@163.com.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, No.15 Changle West Road, Xi'an, Shannxi, 710032, China. y_chen86757@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, No.15 Changle West Road, Xi'an, Shannxi, 710032, China. jinjinyang000@126.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, No.15 Changle West Road, Xi'an, Shannxi, 710032, China. liyizesz@163.com.
authors.forename: Yize
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, No.15 Changle West Road, Xi'an, Shannxi, 710032, China. xueyan_xjh@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xue
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C508587:IL37 protein, human; D007375:Interleukin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A