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Interleukin (IL)‐36α, a newly recognized IL‐1 family member, has been previously reported to play a pivotal role in autoimmunity diseases and acute inflammatory reactions. Recently, several studies have indicated that IL‐36α has potential anticancer effects against certain types of cancer. However, the expression pattern and functional role of IL‐36α in non‐small cell lung cancer (NSCLC) have not been elucidated. Here, we report that the mRNA and protein levels of IL‐36α are significantly reduced in NSCLC tissues. Low levels of intratumoral IL‐36α are correlated with higher tumor status, advanced TNM stage, increased vascular invasion and shorter overall survival (OS). Intratumoral IL‐36α expression is an independent prognostic factor for OS (hazard ratio = 3.081; P = 0.012) in patients with NSCLC. Overexpression of IL‐36α in lung cancer cells did not disturb cell proliferation, apoptosis or cell‐cycle distribution in vitro, but markedly inhibited tumor growth in vivo. Mechanistically, IL‐36α reduced the expression and secretion of vascular endothelial growth factor A through inhibiting hypoxia‐inducible factor 1α expression. Finally, decreased IL‐36α expression was associated with high microvessel density and vascular endothelial growth factor A in patients with NSCLC. Together, our findings suggest that IL‐36α expression is a valuable marker indicating poor prognosis in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths can be attributed to metastatic spread. Lung cancer stem cells (CSCs) are a component of the tumour microenvironment that contributes to this process. Exosomes are small membrane vesicles secreted by all types of cells that mediate cell interactions, including cancer metastasis. Here, we show that lung CSC‐derived exosomes promote the migration and invasion of lung cancer cells, up‐regulate expression levels of N‐cadherin, vimentin, MMP‐9 and MMP‐1, and down‐regulate E‐cadherin expression. Moreover, we verified that these exosomes contribute to a pro‐metastatic phenotype in lung cancer cells via miR‐210‐3p transfer. The results of bioinformatics analysis and dual‐luciferase reporter assays further indicated that miR‐210‐3p may bind to fibroblast growth factor receptor‐like 1 (FGFRL1); silencing FGFRL1 enhanced the metastatic ability of lung cancer cells, whereas overexpressing FGFRL1 suppressed metastasis. Taken together, our results provide new insights into a potential molecular mechanism whereby lung CSC‐derived exosomal miR‐210‐3p targets FGFRL1 to promote lung cancer metastasis. FGFRL1 may be a promising therapeutic target in lung cancer. [ABSTRACT FROM AUTHOR]

Background: With a high frequency of 30%, KRAS mutations in patients with non-small cell lung cancer (NSCLC) often lead to their poor response to most anti-cancer therapies. As a multi-target tyrosine kinase inhibitor, Anlotinib shows clinical efficacy against several types of cancer. However, its effects on KRAS mutant NSCLC and the underlying molecular mechanisms remain unclear. Materials and Methods: Cell counting Kit-8 assay, colony formation assay, flow cytometry analysis, wound healing scratch assay, Transwell assay and xenograft mouse model were used to evaluate the anti-cancer effects of Anlotinib. The potential molecular mechanisms were determined by immunohistochemistry (IHC) and Western blotting. Results: Anlotinib inhibited proliferation of KRAS mutant lung cancer cells and induced apoptosis in vitro. In addition, the migration and invasion abilities of these cells were also decreased after treatment with Anlotinib. It significantly suppressed tumor growth in vivo and prolonged the survival of the xenograft-bearing mice, which correlated to lower expression levels of Ki67 in the tumor tissues. Mechanistically, Anlotinib downregulated MEK and ERK as well as their phosphorylated forms in the KRAS mutant lung cancer cells. Conclusion: Anlotinib inhibits the growth of KRAS mutant lung cancer cells partly via the suppression of the MEK/ERK pathway. Our findings provide novel insights into treating recalcitrant KRAS mutated NSCLC. [ABSTRACT FROM AUTHOR]

IL-9 is a proinflammatory cytokine that plays a critical role in autoimmunity and inflammatory diseases. However, its role in tumorigenesis has not been well studied. In this study, we found that IL-9 expression was significantly increased and associated with poor progression in human non-small cell lung cancer (NSCLC). Ectopic expression of IL-9 in NSCLC cells did not affect cell proliferation and apoptosis in vitro , but markedly promoted tumor growth in vivo. Immune-profile analysis showed no significant changes in the frequencies of infiltrated immune cells in the tumor site, neither in nude mice nor in immune-competent mice. However, we found that VEGF and microvessel density (MVD) were significantly increased in xenografts. IL-9 could promote cell growth and tube formation of HUVEC cells in vitro. In addition, correlation analysis implied a significant positive relationship between the density of IL-9 and VEGF, as well as MVD in human NSCLC tissues. Finally, we found that IL-9 stimulated tumor angiogenesis via STAT3 signaling. Together, our findings demonstrate a promoting role of IL-9 in lung cancer development, probably through promoting tumor angiogenesis. IL-9 thus may represent a new prognostic marker and therapeutic target for NSCLC. • IL-9 expression was increased and associated with poor progression in human NSCLC. • Ectopic expression of IL-9 repressed in vivo tumor growth of NSCLC. • IL-9 promotes tumor angiogenesis via STAT3 signaling. [ABSTRACT FROM AUTHOR]