Circular RNA circTTBK2 facilitates non-small-cell lung cancer malignancy through the miR-873-5p/TEAD1/DERL1 axis.

Aim: The underlying mechanisms by which circular RNAs (circRNAs) regulate non-small-cell lung cancer (NSCLC) progression remain elusive. This study investigated the role of circRNA circTTBK2 in NSCLC tumorigenesis. Materials & methods: Quantitative reverse transcriptase polymerase chain reaction analysis of circTTBK2 in NSCLC tissues and cell lines was performed. Cell proliferation, migration, invasion and tumorigenesis were confirmed in vitro and in vivo using CCK-8, EdU incorporation, Transwell assays and xenograft technique. The circTTBK2/miR-873-5p/TEAD1/DERL1 axis was verified by RNA immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assays. Results: Overexpressed circTTBK2 in NSCLC tissues indicates poor prognosis of NSCLC patients. circTTBK2 harbors miR-873-5p, and miR-873-5p directly targets TEAD1. TEAD1 transcriptionally activates DERL1. Conclusion: This study revealed a novel machinery of circTTBK2/miR-873-5p/TEAD1/DERL1 for NSCLC tumorigenesis.

Oxypeucedanin relieves LPS-induced acute lung injury by inhibiting the inflammation and maintaining the integrity of the lung air-blood barrier.

INTRODUCTION: Acute lung injury (ALI) is commonly accompanied by a severe inflammatory reaction process, and effectively managing inflammatory reactions is an important therapeutic approach for alleviating ALI. Macrophages play an important role in the inflammatory response, and this role is proinflammatory in the early stages of inflammation and anti-inflammatory in the late stages. Oxypeucedanin is a natural product with a wide range of pharmacological functions. This study aimed to determine the effect of oxypeucedanin on lipopolysaccharide (LPS)-induced ALI. METHODS AND RESULTS: In this study, the following experiments were performed based on LPS-induced models in vivo and in vitro. Using myeloperoxidase activity measurement, ELISA, qRT-PCR, and Western blotting, we found that oxypeucedanin modulated the activity of myeloperoxidase and decreased the expression levels of inflammatory mediators such as TNF-α, IL-6, IL-1ß, MPO, COX-2 and iNOS in LPS-induced inflammation models. Meanwhile, oxypeucedanin inhibited the activation of PI3K/AKT and its downstream NF-κB and MAPK signaling pathways. In addition, oxypeucedanin significantly decreased the pulmonary vascular permeability, which was induced by LPSs, and the enhanced expression of tight junction proteins (Occludin and Claudin 3). CONCLUSIONS: In conclusion, this study demonstrated that the anti-inflammatory mechanism of oxypeucedanin is associated with the inhibition of the activation of PI3K/AKT/NF-κB and MAPK signaling pathways and the maintenance of the integrity of the lung air-blood barrier.

MicroRNA-326 impairs chemotherapy resistance in non small cell lung cancer by suppressing histone deacetylase SIRT1-mediated HIF1α and elevating VEGFA.

Compelling evidence has implicated the role of microRNAs (miRs or miRNAs) in lung cancer. Sirtuin-1 (SIRT1) is a key contributor to the progression of non-small cell lung cancer (NSCLC). This study was intended to investigate whether miR-326 affected NSCLC associated with SIRT1. miR-326 and SIRT1 expression in H460 cells and chemoresistant cells H460-R was measured by RT-qPCR. Dual luciferase reporter gene assay and RIP assay were used to identify and validate the relationship between miR-326 and SIRT1. Using gain- and loss-of-function approaches, we evaluated their effects on the chemoresistance of NSCLC cells. ChIP assay was used to detect binding of SIRT1 to the promoter of HIF1α gene, and the binding H3K9Ac to HIF1α, binding of H3K9Ac and HIF1α after silencing SIRT1, and binding HIF1α to VEGFA promoter. In vivo experiments were performed to validate the in vitro findings. MiR-326 expression was decreased while SIRT1 expression was increased in NSCLC cells. SIRT1 was a target of miR-326. MiR-326 inhibited the proliferation of chemotherapy-resistant NSCLC cells and promoted their apoptosis by suppressing SIRT1. In addition, SIRT1 promoted chemoresistance of NSCLC cell by elevating VEGFA expression. Through this mechanism, miR-326 reduced the chemoresistance, which was validated in vivo. Taken together, miR-326 represses SIRT1 through impeding HIF1α expression, thus hindering chemotherapy resistance in lung cancer. These findings provide an exquisite therapeutic target for NSCLC.

Genetic network and gene set enrichment analyses identify MND1 as potential diagnostic and therapeutic target gene for lung adenocarcinoma.

This study aimed to characterize the key survival-specific genes for lung adenocarcinoma (LUAD) using machine-based learning approaches. Gene expression profiles were download from gene expression omnibus to analyze differentially expressed genes (DEGs) in LUAD tissues versus healthy lung tissue and to construct protein-protein interaction (PPI) networks. Using high-dimensional datasets of cancer specimens from clinical patients in the cancer genome atlas, gene set enrichment analysis was employed to assess the independent effect of meiotic nuclear divisions 1 (MND1) expression on survival status, and univariate and multivariate Cox regression analyses were applied to determine the associations of clinic-pathologic characteristics and MND1 expression with overall survival (OS). A set of 495 DEGs (145 upregulated and 350 downregulated) was detected, including 63 hub genes with ≥ 10 nodes in the PPI network. Among them, MND1 was participated in several important pathways by connecting with other genes via 17 nodes in lung cancer, and more frequently expressed in LUAD patients with advancing stage (OR = 1.68 for stage III vs. stage I). Univariate and multivariate Cox analyses demonstrated that the expression level of MND1 was significantly and negatively correlated with OS. Therefore, MND1 is a promising diagnostic and therapeutic target for LUAD.

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.

Relationship of chest CT score with clinical characteristics of 108 patients hospitalized with COVID-19 in Wuhan, China.

BACKGROUND: In December 2019, the outbreak of a disease subsequently termed COVID-19 occurred in Wuhan, China. The number of cases increased rapidly and spread to six continents. However, there is limited information on the chest computed tomography (CT) results of affected patients. Chest CT can assess the severity of COVID-19 and has sufficient sensitivity to assess changes in response to glucocorticoid therapy. OBJECTIVE: Analyze COVID-19 patients to determine the relationships of clinical characteristics, chest CT score, and levels of inflammatory mediators. METHODS: This retrospective, single-center case series of 108 consecutive hospitalized patients with confirmed COVID-19 at Tongji Hospital, Tongji Medical College of HUST (Wuhan, China) examined patients admitted from January 28 to February 20, 2020. Patient demographics, comorbidities, clinical findings, chest CT results, and CT scores of affected lung parenchyma were recorded. The relationships between chest CT score with levels of systemic inflammatory mediators were determined. RESULTS: All patients exhibited signs of significant systemic inflammation, including increased levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, chest CT score, and a decreased lymphocyte (LY) count. Chest CT score had positive associations with white blood cell (WBC) count, CRP, ESR, procalcitonin, and abnormal coagulation function, and a negative association with LY count. Treatment with a glucocorticoid increased the LY count, reduced the CT score and CRP level, and improved coagulation function. CONCLUSIONS: COVID-19 infection is characterized by a systemic inflammatory response that affects the lungs, blood, digestive system, and circulatory systems. The chest CT score is a good indicator of the extent of systemic inflammation. Glucocorticoid treatment appears to reduce systemic inflammation in these patients.

A rare cause of sudden chest pain and dyspnea: A CARE-compliant case report of Chilaiditi syndrome.

RATIONALE: Chilaiditi syndrome is a rare disorder characterized by a broad spectrum of (gastro-intestinal) symptoms caused by interposition of a segment of bowel between the liver and the diaphragm. Most cases present with abdominal symptoms and the morbidity tend to increase with age. PATIENT CONCERNS: Here we present a rare case of Chilaiditi syndrome. An elderly postmenopausal woman developed unresolved postoperative respiratory symptoms and chest pain. Chest auscultation revealed considerable attenuation of respiratory sounds. She showed postoperative increase in D-dimer level and sudden onset of dyspnea. DIAGNOSES: Considering the presence of atelectasis in the middle and lower lobes of the right lung, bedside fiberoptic bronchoscopy was performed immediately to rule out bronchial phlegm embolism. However, no phlegm embolism was found in the left lung, and a small amount of yellow-white mucus was seen in the upper lobe of the right lung. Due to external pressure, the lumen of the middle and lower lobes of the right lung was obviously narrowed. INTERVENTIONS: The patient was placed in a semi-sitting position and a tube was passed through the anus to decompress the intestinal cavity; in addition, she received potassium supplementation. OUTCOMES: The patient's symptoms improved markedly. Chest and semi-supine abdominal plain radiographs showed enhanced lung markings, shadows in the left lower lung lobes, elevation of the right diaphragm, and small amount of pneumoperitoneum. The patient recovered after 5 days of continuous treatment and was discharged. LESSONS: Emergency computed tomographic pulmonary angiography may facilitate the diagnosis of Chilaiditi syndrome, especially in the postoperative setting. Occurrence of Chilaiditi syndrome in this patient was likely associated with surgical factors. Appropriate investigations and clear identification of etiology are essential for successful treatment.

Circular RNAs: pivotal molecular regulators and novel diagnostic and prognostic biomarkers in non-small cell lung cancer.

PURPOSE: Circular RNAs (circRNAs), a large class of non-coding RNAs with covalently closed-loop structures, are abundant, stable, conserved, and have tissue and developmental-stage specificities. The biological functions of circRNAs are varied. Moreover, circRNAs participate in various pathological processes, especially in multiple cancers. Lung cancer is the most frequent malignant tumor worldwide. Many studies have suggested that circRNAs are pivotal in non-small cell lung cancer. This article aims to provide a retrospective review of the latest research on the functions of circRNAs in non-small cell lung cancer. In particular, we focus our discussion on the role of circRNAs in cell-cycle regulation and the epithelial-mesenchymal transition, and also discuss the known regulatory molecular mechanisms of circRNAs in non-small cell lung cancer. METHODS: We reviewed the literature on circRNAs and non-small cell lung cancer from PubMed databases. Specifically, we focused on the roles and mechanisms of circRNAs in regulating the cell cycle and the epithelial-mesenchymal transition. RESULTS: Dysregulation of circRNAs is closely correlated with proliferation, migration, and invasion of non-small cell lung cancer, especially in terms of modulating cell-cycle regulation and the epithelial-mesenchymal transition. CONCLUSION: Taken together, circRNAs have potential as biomarkers for the diagnosis, prognosis, and treatment of non-small cell lung cancer.

Cigarette Smoke Induced Lung Barrier Dysfunction, EMT, and Tissue Remodeling: A Possible Link between COPD and Lung Cancer.

Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide. The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes. These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease. A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer. In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent. In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression. The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death. Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks. Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer. In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer.

Role of RNA-binding protein 5 in the diagnosis and chemotherapeutic response of lung cancer.

Lung cancer remains one of the leading causes of cancer-associated mortality in the world. Lung carcinogenesis is frequently associated with deletions or the loss of heterozygosity at the critical chromosomal region 3p21.3, where RNA-binding protein 5 (RBM5) is localized. RBM5 regulates cell growth, cell cycle progression and apoptosis in cell homeostasis. In the lungs, altered RBM5 protein expression leads to alterations in cell growth and apoptosis, with subsequent lung pathogenesis and varied responses to treatment in patients with lung cancer. Detection of RBM5 expression may be a tumor marker for diagnosis, prediction and treatment response in lung cancer, and may be developed as a potential therapeutic target for drug resistant lung cancer. This review discusses the most recent progress on the role of RBM5 in lung cancer.

Myricetin attenuates LPS-induced inflammation in RAW 264.7 macrophages and mouse models.

AIM: Acute lung injury is a common clinical syndrome associated with significant morbidity. Myricetin has been demonstrated to inhibit inflammation in a variety of diseases. In this study, we aimed to investigate the protective effects of myricetin on inflammation in lipopolysaccharide-stimulated RAW 264.7 cells and lipopolysaccharide-induced lung injury model. Results/methodology: In this study, we detected the anti-inflammatory effects of myricetin by ELISA, RT-PCR and Western blot, respectively. Myricetin significantly inhibited the production of the proinflammatory cytokines in vitro and in vivo. It exerted an anti-inflammatory effect through suppressing the NF-κB p65 and AKT activation in NF-κB pathway and JNK, p-ERK and p38 in MAPK signaling pathway. CONCLUSION: Myricetin alleviated acute lung injury by inhibiting macrophage activation, and inhibited inflammation in vitro and in vivo. It may be a potential therapeutic candidate for the prevention of inflammatory diseases.

The relationship between microRNAs and the STAT3-related signaling pathway in cancer.

MicroRNAs are non-coding RNAs that regulate gene expression by targeting messenger RNA molecules in 3' untranslated region. Mounting evidence indicates that microRNAs regulate several factors to influence various biological activities that are related to carcinogenesis, including signal transducer and activator of transcription 3, which is a transcription factor that also acts as an oncogene. MicroRNAs influence signal transducer and activator of transcription 3 either by directly targeting or via other pathway components upstream or downstream of signal transducer and activator of transcription 3 such as Janus kinases, members of the suppressor of cytokine signaling family, and other genes that regulate cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition. However, signal transducer and activator of transcription 3 activation changes the pattern of expression of microRNAs and mediates tumorigenesis. Moreover, the relationship between signal transducer and activator of transcription 3 and microRNAs varies among different kinds of cancers. A specific microRNA may act as an oncogene or tumor suppressor in different cancers, and microRNAs also directly or indirectly regulate signal transducer and activator of transcription 3 via pathways in the same cancers. In this review, we focus on the reciprocal regulation and roles of microRNAs and signal transducer and activator of transcription 3 in cancer, as well as describe current research progress on this relationship. A better understanding of this relationship may facilitate in the identification of targets for clinical therapeutics.