The progression of lung cancer is majorly facilitated by TAMs (tumour-associated macrophages). However, how the TAMs infiltrate the NSCLC microenvironment and the associated biochemical are not fully elaborated. Research has revealed that changes in CtBP1 modulates innate immunity. Here, we investigated if CtBP1 facilitates infiltration of TAM and the subsequent progression of NSCLC. Immunohistochemical analysis was carried out in 96 NSCLC patients to estimate the clinicopathological importance of CtBP1 in the disease. CtBP1 overexpression and knockdown were carried out to assess the activity of CtBP1 in NSCLC cells. Elevated expression of CtBP1 correlated positively with TAMs infiltration into NSCLC tissues, induced EMT (epithelial-mesenchymal transition) in NSCLC cells and modulated the activated NF-κB signalling pathway leading to increase in CCL2 secretion from NSCLC cells, thus promoting TAM recruitment and polarization. TAM induction and polarization reduced significantly on exhausting p65 in NSCLC cells with CtBP1. Moreover, infiltration of TMAs was reduced remarkably on antagonist-mediated blocking of CCR2 and impeded the progression of NSCLC in a mouse model. These findings thus show a novel insight into the process of CtBP1-regulated TAM infiltration in NSCLC.

Several microRNAs are associated with carcinogenesis and tumour progression. Herein, our observations suggest both miR24-2 and Pim1 are up-regulated in human liver cancers, and miR24-2 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR24-2 increases the expression of N6-adenosine-methyltransferase METTL3 and thereafter promotes the expression of miR6079 via RNA methylation modification. Furthermore, miR6079 targets JMJD2A and then increased the tri-methylation of histone H3 on the ninth lysine (H3K9me3). Therefore, miR24-2 inhibits JMJD2A by increasing miR6079 and then increases H3K9me3. Strikingly, miR24-2 increases the expression of Pim1 dependent on H3K9me3 and METTL3. Notably, our findings suggest that miR24-2 alters several related genes (pHistone H3, SUZ12, SUV39H1, Nanog, MEKK4, pTyr) and accelerates progression of liver cancer cells through Pim1 activation. In particular, Pim1 is required for the oncogenic action of miR24-2 in liver cancer. This study elucidates a novel mechanism for miR24-2 in liver cancer and suggests that miR24-2 may be used as novel therapeutic targets of liver cancer.

Our previous studies demonstrated that high mobility group box-1 (HMGB1), a typical damage-associated molecular pattern (DAMP) protein, is associated with the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Moreover, HMGB1 participates in ANCA-induced neutrophil activation. The current study aimed to investigate whether HMGB1 regulated the interaction between neutrophils and glomerular endothelial cells (GEnC) in the presence of ANCA. Correlation analysis on HMGB1 levels in AAV patients and soluble intercellular cell adhesion molecule-1 (sICAM-1) levels or vascular endothelial growth factor (VEGF) levels, which are markers of endothelial cell activation, was performed. The effect of HMGB1 on neutrophil migration towards GEnC, respiratory burst and degranulation of neutrophils in coculture conditions with GEnC was measured. The activation of neutrophils, the activation and injury of GEnC, and the consequent pathogenic role of injured GEnC were evaluated. Plasma levels of HMGB1 correlated with sICAM-1 and VEGF (r = 0.73, P < 0.01; r = 0.41, P = 0.04) in AAV patients. HMGB1 increased neutrophil migration towards GEnC, as well as respiratory burst and degranulation of neutrophils in the presence of ANCA in the coculture system. In the presence of robust neutrophil activation, GEnC were further activated and injured in the coculture system of GEnC and neutrophils. In addition, injured GEnC could produce TF-positive leuco-endothelial microparticles and endothelin-1 (ET-1), while NF-κB was phosphorylated (S529) in the injured GEnC. Plasma levels of HMGB1 correlated with endothelial cell activation in AAV patients. HMGB1 amplified neutrophil activation and the activation and injury of GEnC in the presence of ANCA.

Myeloid-derived growth factor (MYDGF) is a novel protein secreted by bone marrow cells that features important physiological functions. In recent years, MYDGF has gained considerable interest due to their extensive beneficial effect on cardiac repair and protects cardiomyocytes from cell death. However, its precise molecular mechanisms have not been well elucidated. The purpose of this study was to produce sufficient amount of biologically active recombinant human (rh) MYDGF more economically and effectively by using in vitro molecular cloning techniques to study its clinical application. The prokaryotic expression system of Escherichia coli was established for the preparation of rhMYDGF. Finally, a large amount of high biologically active and purified form of recombinant protein was obtained. Moreover, we investigated the potential mechanism of rhMYDGF-mediated proliferation and survival in human coronary artery endothelial cells (HCAECs). Mechanistically, the results suggested that MAPK/STAT3 and the cyclin D1 signalling pathways are indispensable for rhMYDGF-mediated HCAEC proliferation and survival. Therefore, this study successfully established a preparation protocol for biologically active rhMYDGF and it may be a most economical way to produce high-quality active rhMYDGF for future clinical application.

T cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive haematological cancer of the bone marrow. The abnormal expression of microRNAs (miRNAs) is reportedly involved in T-ALL development and progression. Thus, we aimed to decipher the involvement of miR-204 silencing mediated by DNA methylation in the occurrence of T cell acute lymphoblastic leukaemia (T-ALL). miR-204 expression was determined in bone marrow and peripheral blood samples from T-ALL patients by real-time quantitative PCR (RT-qPCR) with its effect on cell proliferation evaluated by functional assays. In addition, bisulphite sequencing PCR was employed to detect the DNA methylation level of the miR-204 promoter region, and the binding site between miR-204 and IRAK1 was detected by luciferase assay. We found that miR-204 was down-regulated in T cells of T-ALL patients, which was caused by the increased DNA methylation in the promoter region of miR-204. Moreover, overexpression of miR-204 inhibited T-ALL cell proliferation while enhancing their apoptosis through interleukin receptor-associated kinase 1 (IRAK1), which enhanced the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 through activation of p-p65. Thus, miR-204 modulated MMP-2 and MMP-9 through IRAK1/NF-κB signalling pathway, which was confirmed by in vivo assay. Taken together, DNA methylation-mediated miR-204 silencing increased the transcription of IRAK1, thus activating the NF-κB signalling pathway and up-regulating the downstream targets MMP-2/MMP-9.

Deregulation of the basic helix-loop-helix family member e41 (BHLHE41) has been characterized as a marker of progression of several cancers. In this study, we aimed to explore the mechanism by which BHLHE41 regulates the invasion of breast cancer cells. BHLHE41 suppresses, whereas the silencing of BHLHE41 promotes tumour invasion of both MCF-7 and MDA-MB-231 cells. Meanwhile, BHLHE41 down-regulated the transcription and translation of SNAI1, SNAI2, VIM and CDH2, and up-regulated those of CLDN1, CLDN4 and CDH1. Reporter assay indicated that silencing of BHLHE41 dramatically activated the MAPK/JNK signalling pathway in MCF-7 cell line and the hypoxia signalling pathway in MDA-MB-231 cell line. Furthermore, silencing of BHLHE41 activated the MAPK/JNK signalling pathway by up-regulating phosphorylated JNK and failed to affect the expression of HIF-1 alpha in MCF-7 cells. After blocking the MAPK/JNK signalling pathway by specific inhibitor SP600125, silencing of BHLHE41 failed to promote tumour cell invasion. These results suggest that BHLHE41 facilitates MCF-7 cell invasion mainly via the activation of MAPK/JNK signalling pathway. In conclusion, although BHLHE41 suppresses tumour invasion in MCF-7 and MDA-MB-231 cell lines, the specific regulatory mechanisms may be different.

Toll-like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone-lysine N-methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9-heterochromatin protein 1-telomere repeat binding factor 2 (H3K9me3-HP1-TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer-associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1α and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat-containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri-complexes of HP1 isoforms (α, β and γ) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer.

DEP domain containing 1(DEPDC1) is involved in the tumorigenesis of a variety of cancers. But its role in tumorigenesis of lung adenocarcinoma (LUAD) is not fully understood. Here, we investigated the role and the underlying mechanisms of DEPDC1 in the development of LUAD. The expression and prognostic values of DEPDC1 in LUAD were analysed by using the data from public databases. Gene enrichment in TCGA LUAD was analysed using GSEA software with the pre-defined gene sets. Cell proliferation, migration and invasion of A549 cells were examined with colony formation, Transwell and wound healing assays. The function of DEPDC1 in autophagy and RAS-ERK1/2 signalling was determined with Western blot assay upon DEPDC1 knockdown and/or overexpression in A549, HCC827 and H1993 cells. The results demonstrated that DEPDC1 expression was up-regulated in LUAD tissues, and its high expression was correlated with unfavourable prognosis. The data also showed that DEPDC1 knockdown impaired proliferation, migration and invasion of A549 cells. Most notably, the results showed that DEPDC1 up-regulated RAS expression and thus enhanced ERK1/2 activity, through which DEPDC1 could inhibit autophagy. In conclusion, our study revealed that DEPDC1 is up-regulated in LUAD tissues and plays an oncogenic role in LUAD, and that DEPDC1 inhibits autophagy through the RAS-ERK1/2 signalling in A549, HCC827 and H1993 cells.

Obesity-induced activation and proliferation of resident macrophages and infiltration of circulating monocytes in adipose tissues contribute to adipose tissue inflammation and insulin resistance. These effects further promote the development of metabolic syndromes, such as type 2 diabetes, which is one of the most prevalent health conditions severely threatening human health worldwide. Our study examined the potential molecular mechanism employed by fibroblast growth factor 1 (FGF1) to improve insulin sensitivity. The leptin receptor-deficient obese mice (db/db) served as an insulin-resistant model. Our results demonstrated that FGF1-induced amelioration of insulin resistance in obese mice was related to the decreased levels of pro-inflammatory adipose tissue macrophages (ATMs) and plasma inflammatory factors. We found that FGF1 enhanced the adipocyte mTORC2/Rictor signalling pathway to inhibit C-C chemokine ligand 2 (CCL2) production, the major cause of circulating monocytes infiltration, activation and proliferation of resident macrophages in adipose tissues. Conversely, these alleviating effects of FGF1 were substantially abrogated in adipocytes with reduced expression of mTORC2/rictor. Furthermore, a model of adipocyte-specific mTORC2/Rictor-knockout (AdRiKO) obese mice was developed to further understand the in vitro result. Altogether, these results demonstrated adipocyte mTORC2/Rictor was a crucial target for FGF1 function on adipose tissue inflammation and insulin sensitivity.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with multiple molecular mechanisms. To investigate and contrast the molecular processes differing between bronchiolitis and emphysema phenotypes of COPD, we downloaded the GSE69818 microarray data set from the Gene Expression Omnibus (GEO), which based on lung tissues from 38 patients with emphysema and 32 patients with bronchiolitis. Then, weighted gene coexpression network analysis (WGCNA) and differential coexpression (DiffCoEx) analysis were performed, followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis (KEGG) analysis. Modules and hub genes for bronchiolitis and emphysema were identified, and we found that genes in modules linked to neutrophil degranulation, Rho protein signal transduction and B cell receptor signalling were coexpressed in emphysema. DiffCoEx analysis showed that four hub genes (IFT88, CCDC103, MMP10 and Bik) were consistently expressed in emphysema patients; these hub genes were enriched, respectively, for functions of cilium assembly and movement, proteolysis and apoptotic mitochondrial changes. In our re-analysis of GSE69818, gene expression networks in relation to emphysema deepen insights into the molecular mechanism of COPD and also identify some promising therapeutic targets.

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)-17A has been demonstrated to have a pro-fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL-17 receptor A (IL-17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)-induced PF murine model. We found that IL-17A knockout (IL-17A-/- ) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL-17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN-induced putative kinase 1 (PINK1)/Parkin signal-mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL-17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL-17A exerts its pro-fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1-mediated mitophagy, thereby leading to apoptosis of AECIIs.