Oncogenic lncRNA MALAT-1 recruits E2F1 to upregulate RAD51 expression and thus promotes cell autophagy and tumor growth in non-small cell lung cancer.

INTRODUCTION: LncRNA MALAT-1 expression is involved in regulating activities of non-small-cell lung cancer (NSCLC) cells. This study aimed to investigate the effects of lncRNA MALAT-1 on chemosensitivity of NSCLC cells by regulating autophagy. METHODS: We first validated the expression of lncRNA MALAT-1 in NSCLC cell lines. NSCLC cell lines with high lncRNA MALAT-1 expression were exposed to doxorubicin (DOX) to assess chemosensitivity. Further LncMAP database retrieval and ChIP, RIP and luciferase activity assays were conducted to explore interplay between lncRNA MALAT-1, RAD51, and E2F1. Immunofluorescence staining was performed to evaluate formation of autophagosomes in NSCLC cells. Ectopic expression and knockdown methods were used for in vitro mechanism experiments and in vivo substantiation. RESULTS: LncRNA MALAT-1 was overexpressed in NSCLC cells, and could promote NSCLC cell autophagy and inhibit its chemosensitivity. In vitro cell mechanism verification experiments showed that lncRNA MALAT-1 could recruit transcription factor E2F1 to bind to the promoter of RAD51, so as to promote the transcriptional expression of RAD51. In addition, cell function experiments in vitro showed that ectopically expressed lncRNA MALAT-1 promoted NSCLC cell autophagy and inhibited its chemosensitivity, while RAD51 knockdown negated its effect. Finally, in vivo animal experiments confirmed that lncRNA MALAT-1 silencing could impede the tumor growth. CONCLUSIONS: Taken together, this study revealed that silencing lncRNA MALAT-1 enhanced chemosensitivity of NSCLC cells by promoting autophagy, highlighting a feasible approach to prevent chemoresistance in NSCLC treatment.

Role of HDAC6 inhibition in sepsis-induced acute respiratory distress syndrome (Review).

Acute respiratory distress syndrome (ARDS) induced by sepsis contributes remarkably to the high mortality rate observed in intensive care units, largely due to a lack of effective drug therapies. Histone deacetylase 6 (HDAC6) is a class-IIb deacetylase that modulates non-nuclear protein functions via deacetylation and ubiquitination. Importantly, HDAC6 has been shown to exert anti-cancer, anti-neurodegeneration, and immunological effects, and several HDAC6 inhibitors have now entered clinical trials. It has also been recently shown to modulate inflammation, and HDAC6 inhibition has been demonstrated to markedly suppress experimental sepsis. The present review summarizes the role of HDAC6 in sepsis-induced inflammation and endothelial barrier dysfunction in recent years. It is proposed that HDAC6 inhibition predominantly ameliorates sepsis-induced ARDS by directly attenuating inflammation, which modulates the innate and adaptive immunity, transcription of pro-inflammatory genes, and protects endothelial barrier function. HDAC6 inhibition protects against sepsis-induced ARDS, thereby making HDAC6 a promising therapeutic target. However, HDAC inhibition may be associated with adverse effects on the embryo sac and oocyte, necessitating further studies.

circ_001504 promotes the development of renal cell carcinoma by sponging microRNA-149 to increase NUCB2.

Renal cell carcinoma (RCC) accounts for over 90% of primary renal tumors in adults. Although treatment approaches have steadily improved over the years, the prognosis outcome remains poor. With the aim of developing novel targets for RCC treatment, we explored the role of the circular RNA (circRNA) circ_001504 in the progression of RCC. We initially detected the expression of circ_001504 and microRNA (miRNA)-149 in RCC tissues and cells. RT-qPCR results showed that circ_001504 was highly expressed in RCC tissues, whereas miR-149 was poorly expressed. Interestingly, downregulation of circ_001504 suppressed malignant phenotypes in RCC cells, and upregulation of miR-149 exerted a similar effect. Bioinformatics analysis suggested potential binding sites between circ_001504 and miR-149, verified by a dual-luciferase reporter gene assay. Next, we identified nucleobindin 2 (NUCB2), a calcium-binding protein, as a target gene of miR-149. Furthermore, our data suggested that circ_001504 might serve as a competing endogenous RNA of miR-149, serving to elevate the expression of NUCB2. The silencing of circ_001504 resulted in decreased NUCB2 expression, which could be reversed by miR-149 inhibition. In addition, in vivo experiments demonstrated that circ_001504 depletion could suppress tumor growth in an established mouse RCC model. Collectively, reduced expression of circ_001504 lowered NUCB2 expression by sponging miR-149, thereby attenuating RCC progression, providing insight into circ_001504/miR-149/NUCB2 feedback loop into RCC treatment.

miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in tumor microenvironment and favor solid tumor growth. Herein, we aim to characterize the role of miR-21 in regulating the accumulation and activity of MDSCs in lung cancer. METHODS: The proportions of MDSCs, T helper cells (Th), and cytotoxic T lymphocytes (CTL) were evaluated by flow cytometric analyses of peripheral blood and tumor tissues collected from Lewis lung-cancer-bearing mice. T cell proliferation assay was performed in CD4+ or CD8+ T cells cocultured with MDSCs. MDSC apoptosis was examined by flow cytometric analysis. The levels of IL-10, TGF-ß, and GM-CSF in mouse serum were determined by ELISA. miR-21 targeting RUNX1 and RUNX1 interaction with YAP were evaluated by RIP, dual-luciferase reporter gene, and ChIP assays. RESULTS: MiR-21 inhibition by its antagomir reduced the proportion of MDSCs, increased the proportion of Th and CTL in peripheral blood and tumor tissues of Lewis lung-cancer-bearing mice, protected Th and CTL from the suppression of MDSCs, increased apoptosis of MDSCs, but reduced IL-10, TGF-ß and GM-CSF levels in mouse serum. RUNX1 could transcriptionally inhibit the YAP expression, whereas miR-21 targeting RUNX1 led to elevated YAP expression levels. Mechanistic investigation showed that miR-21 maintained MDSC accumulation in tumor microenvironment and promoted immunosuppressive ability of MDSCs in Lewis lung-cancer-bearing mice by down-regulating RUNX1and up-regulating YAP. CONCLUSIONS: Taken together, the study provides evidence that targeting miR-21 in MDSCs may be developed as an immunotherapeutic approach to combat lung cancer development.

The Possible Pathogenesis of Idiopathic Pulmonary Fibrosis considering MUC5B.

BACKGROUND: Overexpression of the MUC5B protein is associated with idiopathic pulmonary fibrosis (IPF), but little information is available regarding the pathogenic effects and regulatory mechanisms of overexpressed MUC5B in IPF. MAIN BODY: The overexpression of MUC5B in terminal bronchi and honeycomb cysts produces mucosal host defensive dysfunction in the distal airway which may play an important role in the development of IPF. This review addresses the possible association of overexpression of MUC5B, with MUC5B promoter polymorphism, MUC5B gene epigenetic changes, effects of some transcriptional factors, and inflammatory mediators in IPF. In addition, the associated signaling pathways which may influence the expression of MUC5B are also discussed. CONCLUSION: This work has important implications for further exploration of the mechanisms of overexpression of MUC5B in IPF, and future personalized treatment.

A novel circular RNA hsa_circ_0020123 exerts oncogenic properties through suppression of miR-144 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide, while circulatory. Circular RNAs (circRNAs) are found to play important roles in cancer initiation and development. Herein, a novel functional circRNA hsa_circ_0020123 had been identified in NSCLC progression in this study, and elevated hsa_circ_0020123 expression could be observed in cancer tissues compared with that in matched normal lung tissues. Moreover, up-regulation of hsa_circ_0020123 was recognized to be closely associated with a poor differentiation degree, lymph node metastasis, a high TNM stage and dismal prognosis for NSCLC patients. Typically, knockdown of hsa_circ_0020123 could inhibit the NSCLC growth and metastasis both in vitro and in vivo, which could be reversed by the hsa_circ_0020123 overexpression. Importantly, miR-144 was identified as the hsa_circ_0020123-associated miRNA through performing RNA in vivo precipitation (RIP) in NSCLC cells using a biotin-labeled hsa_circ_0020123 probe. Besides, our results suggested that, miR-144 suppression had determined the oncogenic properties mediated by hsa_circ_0020123. In addition, hsa_circ_0020123 could upregulate ZEB1 and EZH2 through competitively binding with miR-144. Finally, the administration of hsa_circ_0020123 siRNA could suppress the growth and metastasis in NSCLC-bearing mice in vivo. In conclusion, the hsa_circ_0020123-miR-144-ZEB1/EZH2 axis is critical for NSCLC progression, which indicates that hsa_circ_0020123 is a potential target for NSCLC treatment.