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Previous studies have demonstrated the tumor-suppressive function of microRNA-22-3p (miR-22-3p) in several cancers, whereas the significance of miR-22-3p in non-small cell lung cancer (NSCLC) remains unclear. In this study, we explored the biological function and molecular mechanism of miR-22-3p in NSCLC cells. First, we assessed the expression of miR-22-3p in NSCLC tissues and cells based on RT-qPCR and TCGA database. Compared with normal lung tissues and cells, miR-22-3p expression was dramatically decreased in lung cancer tissues and cells. miR-22-3p expression was also correlated with lymph node metastasis and tumor size, but not TNM stages. We further explored the in vitro function of miR-22-3p on the migration and epithelial–mesenchymal transition (EMT) of NSCLC cells. The results showed that overexpression of miR-22-3p suppressed the migration and EMT of NSCLC cells, whereas silencing miR-22-3p showed the opposite effect. Luciferase assay demonstrated that RAS-related C3 botulinum toxin substrate 1 (RAC1) was the target gene for miR-22-3p. Mechanistically, we demonstrated that miR-22-3p suppressed the cell migration and EMT via downregulation of RAC1 because the inhibitory effect of miR-22-3p on cell migration and EMT of NSCLC cells was reversed by RAC1 overexpression. Based on these novel data, the miR-22-3p/RAC1 axis may be an alternative target in the therapeutic intervention of NSCLC. [ABSTRACT FROM AUTHOR]

Inappropriate accumulation of alveolar macrophages (AMs) and subsequent excessive production of immune responses play critical roles in the pathogenesis of acute lung injury (ALI), but the core negative regulators governing innate signalling in AMs are ill defined. We have previously shown that single immunoglobin IL‐1 receptor‐related protein (SIGIRR), a negative regulator of IL‐1 receptor and Toll‐like receptor signalling, inhibits lipopolysaccharide (LPS)‐induced inflammatory responses in AMs. To address the biological relevance of SIGIRR in vivo, we generated a murine ALI model via intratracheal instillation of LPS. Intriguingly, SIGIRR expression was observed to be decreased in resident and recruited macrophages during ALI. This decrease was associated with parallel induction in CD18 protein levels in LPS‐challenged lung tissues. Through intranasal injection of SIGIRR lentiviral particles studies, we showed that the overexpression of SIGIRR attenuated recruitment of macrophages and neutrophils, decreased production of inflammatory cytokines and ameliorated pathological changes in lungs. Whilst exploring the basis for this phenotype, SIGIRR was found to be coexpressed with CD18 in AMs, and SIGIRR potentiated the instability of CD18 protein via enhancement of its ubiquitination and proteasome degradation. Conversely, by using CD18−/− mice, we further observed that CD18 deletion completely abolished the therapeutic effects of overexpression of SIGIRR on LPS‐induced ALI. Mover, overexpression of CD18 in AMs promoted adhesion to ECM components, enhanced TLR4‐mediated inflammasome activation and thereby potentiated IL‐1β production. These data collectively identify SIGIRR/CD18 as a key negative regulatory circuit maintaining innate immune homeostasis in AMs along the pathogenesis of ALI. [ABSTRACT FROM AUTHOR]

In this study, the effects of single immunoglobin IL-1 receptor-related protein (SIGIRR) on tumor necrosis factor- (TNF-) receptor-associated factor 6 (TRAF6) ubiquitination in acute lung injury (ALI) were evaluated in both alveolar epithelial cells and alveolar macrophage cells in vitro. Our results found that SIGIRR negatively regulated TRAF6 ubiquitination and such SIGIRR inhibition could enhance the TRAF6 expression in both alveolar epithelial cells (AECs) and alveolar macrophage cells (AMCs). SIGIRR knockdown may increase NF-κB activity via TRAF6 regulation by the classical but not the nonclassical NF-κB signaling pathway. Such modulation between TRAF6 and SIGIRR could affect cytokine secretion and exacerbate the immune response; the IL-8, NFKB1, and NFKBIA mRNA levels were reduced after SIGIRR overexpression. The current study reveals the molecular mechanisms of the negative regulatory roles of SIGIRR on the innate immune response related to the LPS/TLR-4 signaling pathway and provides evidence for strategies to clinically treat inflammatory diseases. [ABSTRACT FROM AUTHOR]

Reprogramming of the tumor immune microenvironment is a salient feature during metastasis in LUAD. miR-24-3p and KLF8, which are key regulators of the tumor immune microenvironment, had been proved to show metastasis-promoting property in LUAD. However, whether miR-24-3p could regulate LUAD metastasis by targeting KLF8 remains unclear. This study explored the functions and mechanisms of miR-24-3p/KLF8 signaling in advanced LUAD. The expression level of miR-24-3p and KLF8 were tested in LUAD patients, and the corelation of miR-24-3p and KLF8 was evaluated. The interaction of miR-24-3p and KLF8 was demonstrated by luciferase reporter activity assay, in vitro migration and invasion studies, and in vivo metastatic studies. miR-24-3p level was downregulated in LUAD and negatively associated with KLF8 mRNA expression. miR-24-3p controls LUAD metastasis by directly targeting KLF8 and inducing Snail and E-cadherin expressions. Targeting the miR-24-3p/KLF8/EMT axis might be of great therapeutic value to advanced LUAD patients. [ABSTRACT FROM AUTHOR]

Background: Discussions regarding the correlations between long non-coding RNAs (lncRNAs) and cancers have dominated research in recent years. SIK1-LNC, a type of lncRNA and adjacent to salt-inducible kinases 1 (SIK1), has been found aberrantly expressed in lung cancer. However, its functional role in lung cancer remains largely unknown. Purpose: In this study, we aimed to explore the association between SIK1-LNC expression and SIK1 in lung cancer cells and further identify the impact of SIK1-LNC on the proliferation, migration invasion of lung cancer cells. Patients and methods: Of the 30 patients with non-small-cell lung carcinoma from Zhongnan Hospital of Wuhan University, RT-qPCR was performed to detect SIK1 and SIK1-LNC expressions in patients' samples. Overexpression and knockdown experiments were conducted to analyze the SIK1 and SIK1-LNC expressions in lung cancer cell lines. CCK-8, Brdu, scratch wound-healing, and Transwell assays were respectively employed to evaluate the proliferative, migrative, and invasive abilities of lung cancer cells. Results: Both SIK1-LNC and SIK1 expression levels were evidently downregulated in 30 lung cancer tissues. SIK1-LNC expression was bound up with clinicopathologic features, including lymph node metastasis and distant metastasis. SIK1 expression showed a positive tendency with SIK1-LNC expression in lung cancer cells. SIK1-LNC exerted a significant repression on cell proliferatiive, miogrative and invasive abilities of lung cancer cells. Conclusion: Our findings suggested that SIK1-LNC may act as a novel biomarker and therapeutic target for lung cancer. [ABSTRACT FROM AUTHOR]

Introduction: Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4–ALK) is identified as an important pathogenic factor in patients with non-small-cell lung cancer (NSCLC) and could induce a stem-like phenotype in NSCLC cells. Crizotinib is commonly used for EML4–ALK+ NSCLC treatment, but its acquired resistance results in tumor recurrence. Long intergenic noncoding RNA, regulator of reprogramming (lincROR) is related to the acquisition and maintenance of self-renewal and stemness features of cancer stem cells. It has been documented that lincROR is implicated in chemoresistance. However, the correlations of lincROR and EML4–ALK in stem cell-like properties and of lincROR and crizotinib resistance in NSCLC cells are yet to be elucidated. Patients and methods: In the present study, we investigated the expression profile of lincROR in EML–ALK NSCLC tissues, and the potential role of lincROR in prognosis was then analyzed. Subsequently, its association with stem cell-like properties of EML–ALK+ NSCLC cells was determined. Furthermore, the correlation of lincROR with crizotinib and the effects of lincROR and crizotinib on cell viability of EML4–ALK+ NSCLC cells were all explored. Results: The results showed that lincROR expression was upregulated in EML4–ALK+ NSCLC tissues relative to EML4–ALK− NSCLC tissues. Low-expressed lincROR was related to a favor-able prognosis of patients with EML–ALK NSCLC. lincROR overexpression could enhance the stemness features of EML–ALK+ NSCLC cells which were repressed by ALK knockdown. Conclusion: We found that lincROR expression was significantly inhibited because of the increased concentration of crizotinib in EML4–ALK+ NSCLC cells. Furthermore, lincROR overexpression increased cell viability of EML4–ALK+ NSCLC cells, which was impaired by crizotinib. Conjointly, these results suggested the important role of lincROR in EML–ALK+NSCLC. lincROR may serve as a potential therapeutic target to overcome chemotherapy resistance in EML–ALK+ NSCLC. [ABSTRACT FROM AUTHOR]

This work is aimed at investigating the effect of melittin on identified key genes in bladder cancer (BC) and further providing a theoretical basis for BC treatment. GSE35014 downloaded from the Gene Expression Omnibus (GEO) database was used to screen differentially expressed genes (DEGs) in BC cells and control. Results showed that a total of 389 upregulated and 169 downregulated genes were identified. Subsequently, GO analysis, KEGG pathway enrichment analysis, and PPI network analysis were employed to disclose the crucial genes and signaling pathways involved in BC. Fifteen module-related DEGs and their associated signaling pathways were obtained according to the PPI network and modular analyses. Based on the analysis of articles retrieved in the PubMed database, we found that melittin could induce apoptosis and constrain the progression of tumor cells as a result of regulating critical cancer-related signaling pathways, such as PI3K-Akt and TNF signaling pathways. Furthermore, PI3K-Akt and TNF signaling pathways were also found to be associated with module-related DEGs according to biological analyses. At last, qRT-PCR analysis demonstrated that melittin could constrain the expression of module-related DEGs (LPAR1, COL5A1, COL6A2, CXCL1, CXCL2, and CXCL3) associated with PI3K-Akt and TNF signaling pathways in BC cells. Functional assays revealed that melittin could constrain the proliferative and migrated abilities of BC cells. Conjointly, these findings provide a theoretical basis for these six genes as drug-sensitive markers of melittin in BC treatment. [ABSTRACT FROM AUTHOR]

Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3) contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (n = 22, n = 78). A panel of biochemical assays and functional experiments was utilized to elucidate the underlying mechanisms and effects of FGFR3 and miR-24-3p on lung adenocarcinoma progression. Upregulated FGFR3 expression indicated an adverse prognosis for lung adenocarcinoma individuals and promoted metastatic potential of lung adenocarcinoma cells. Owing to the direct regulation towards FGFR3, miR-24-3p could interfere with the potential of proliferation, migration, and invasion in lung adenocarcinoma, following variations of EMT-related protein expression. As a significant marker of EMT, E-cadherin was negatively correlated with FGFR3, of which ectopic overexpression could neutralize the antitumour effects of miR-24-3p and reverse its regulatory effects on EMT markers. Taken together, these findings define a novel insight into the miR-24-3p/FGFR3 signaling axis in regulating lung adenocarcinoma progression and suggest that targeting the miR-24-3p/FGFR3 axis could be an effective and efficient way to prevent tumor progression. [ABSTRACT FROM AUTHOR]

Background. As acute lung injury (ALI) caused high mortality rate, it is important to explore the protection and treatment of ALI. The aim of the current study is to evaluate the effect of low molecular weight heparin (LMWH) nebulization on attenuating acute lung injury and the associated mechanism. Methods. The arterial blood gas, total protein content in bronchoalveolar lavage fluid, lung wet/dry weight ratio, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and Akt phosphorylation were evaluated after the ALI rabbits were treated with or without LMWH nebulization. Results. PaO2 was increased and lung wet/dry weight ratio as well as total protein content in BALF was decreased after LMWH nebulization. After the application of LMWH nebulization therapy, the SOD and GSH-Px activity was rebounded and the increase of MDA content was significantly inhibited. The Akt protein phosphorylation level was decreased after LMWH nebulization therapy. Conclusions. LMWH nebulization treatment can relieve the traumatic ALI in rabbits and inhibit oxidative stress possibly by suppressing the Akt phosphorylation. [ABSTRACT FROM AUTHOR]

Alveolar macrophages exist in the lung airspaces, and their differentiation and function are considerably regulated by the microenvironment. In this study, we examine the important role of resident neutrophil/ IL-23/granulocyte/macrophage colony-stimulating factor ( GM- CSF) axis in the development and preferential phenotype of alveolar macrophages under physiological conditions. Using CD18-deficient ( CD18 −/−) mice, we show a correlation between increased granulopoiesis and enhanced alveolar macrophage development in an IL-23- and GM- CSF-dependent manner. The apoptotic neutrophils could inhibit the secretion of IL-23 from alveolar macrophages, which is important for the production of GM- CSF, and depletion of neutrophils disrupted the regulation of IL-23 and GM- CSF. This study reveals a mechanism for the regulation of the local alveolar macrophage population and function by neutrophil apoptosis in the circulatory system. [ABSTRACT FROM AUTHOR]