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Background: Noncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases. Non-small cell lung cancer (NSCLC) is one of the most common malignant cancers. Information on the functions and mechanism of circRNAs in lung cancer is limited; thus, the topic needs more exploration. The purpose of this study was to identify aberrantly expressed circRNAs in lung cancer, unravel their roles in NSCLC progression, and provide new targets for lung cancer diagnosis and therapy. Methods: High-throughput sequencing was used to analyze differential circRNA expression in patients with lung cancer. qRT‒PCR was used to determine the level of circHERC1 in lung cancer tissues and plasma samples. Gain- and loss-of-function experiments were implemented to observe the impacts of circHERC1 on the growth, invasion, and metastasis of lung cancer cells in vitro and in vivo. Mechanistically, dual luciferase reporter assays, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circHERC1. Nucleocytoplasmic localization of FOXO1 was determined by nucleocytoplasmic isolation and immunofluorescence. The interaction of circHERC1 with FOXO1 was verified by RNA pull-down, RNA immunoprecipitation (RIP) and western blot assays. The proliferation and migration of circHERC1 in vivo were verified by subcutaneous and tail vein injection in nude mice. Results: CircHERC1 was significantly upregulated in lung cancer tissues and cells, ectopic expression of circHERC1 strikingly facilitated the proliferation, invasion and metastasis, and inhibited the apoptosis of lung cancer cells in vitro and in vivo. However, knockdown of circHERC1 exerted the opposite effects. CircHERC1 was mainly distributed in the cytoplasm. Further mechanistic research indicated that circHERC1 acted as a competing endogenous RNA of miR-142-3p to relieve the repressive effect of miR-142-3p on its target HMGB1, activating the MAPK/ERK and NF-κB pathways and promoting cell migration and invasion. More importantly, we found that circHERC1 could bind FOXO1 and sequester it in the cytoplasm, adjusting the feedback AKT pathway. The accumulation of FOXO1 in the cytosol and nuclear exclusion promoted cell proliferation and inhibited apoptosis. CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential prognostic biomarker and therapeutic target for NSCLC. Conclusions: CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential diagnosis biomarker and therapeutic target for NSCLC. Our findings indicate that circHERC1 facilitates the invasion and metastasis of NSCLC cells by regulating the miR-142-3p/HMGB1 axis and activating the MAPK/ERK and NF-κB pathways. In addition, circHERC1 can promote cell proliferation and inhibit apoptosis by sequestering FOXO1 in the cytoplasm to regulate AKT activity and BIM transcription. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by chronic inflammation and airway remodeling. Human epididymis protein 4 (HE4) plays a critical role in various inflammatory or fibrotic diseases. However, the role of HE4 in COPD remains unidentified.Methods: HE4 expression was determined in the lung tissues from COPD patients and cigarette smoke (CS)-exposed mice using immunohistochemical staining, qPCR, or western blot. The plasma level of HE4 was detected by ELISA. The regulations of HE4 in the expressions of CS extract (CSE)-induced inflammatory cytokines in human bronchial epithelial cells (HBE) were investigated through knockdown or overexpression of HE4. The role of secretory HE4 (sHE4) in the differentiation and proliferation in human pulmonary fibroblast cells (HPF) was explored via qPCR, western blot, CCK8 assay or 5-ethynyl-2'-deoxyuridine (EdU) staining. The probe of related mechanism in CSE-induced HE4 increase in HBE was conducted by administrating N-acetylcysteine (NAC).Results: HE4 was up-regulated in both the lung tissue and plasma of COPD patients relative to controls, and the plasma HE4 was negatively associated with lung function in COPD patients. The same enhanced HE4 expression was verified in CS-exposed mice and CSE-induced HBE, but CSE failed to increase HE4 expression in HPF. In vitro experiments showed that reducing HE4 expression in HBE alleviated CSE-induced IL-6 release while overexpressing HE4 facilitated IL-6 expression, mechanistically through affecting phosphorylation of NFκB-p65, whereas intervening HE4 expression had no distinctive influence on IL-8 secretion. Furthermore, we confirmed that sHE4 promoted fibroblast-myofibroblast transition, as indicated by promoting the expression of fibronectin, collagen I and α-SMA via phosphorylation of Smad2. EdU staining and CCK-8 assay demonstrated the pro-proliferative role of sHE4 in HPF, which was further confirmed by enhanced expression of survivin and PCNA. Pretreatment of NAC in CSE or H2O2-induced HBE mitigated HE4 expression.Conclusions: Our study indicates that HE4 may participate in airway inflammation and remodeling of COPD. Cigarette smoke enhances HE4 expression and secretion in bronchial epithelium mediated by oxidative stress. Increased HE4 promotes IL-6 release in HBE via phosphorylation of NFκB-p65, and sHE4 promotes fibroblastic differentiation and proliferation. [ABSTRACT FROM AUTHOR]

Background: To identify COPD associated gene susceptibility and lung function in a longitudinal cohort including COPD and subjects who were at risk for developing COPD, and to replicate this in two cross-sectional and longitudinal populations in Chinese Han population.Methods: Three cohorts were recruited in this study, including an 18-year follow-up population (306 COPD and 743 control subjects) in one village in 1992 and it changed to 409 COPD and 611 controls in 2010, a 2 year follow-up study in another village (374 COPD and 377 controls) and another 2 year follow-up one in a city (541 COPD and 560 controls) in 2010. Sixteen candidate single nucleotide polymorphisms (SNPs) were selected for genotyping. Among them, 5SNPs in or near HHIP, 1SNP in IREB2 and 1SNP in FAM13A were previously reported to be associated with COPD susceptibility or lung function decline. And another 9SNPs were selected from HapMap website as HHIP tags. In 2010, totaling 1,324 COPD patients and 1,548 healthy controls were finally included in our genetic susceptibility analyses.Results: We identified two new regions showing an association with COPD susceptibility in the Human Hedgehog interacting protein (HHIP) rs11100865 and rs7654947, and we confirmed that the family with sequence similarity 13 member A gene (FAM13A) rs7671167 was associated with the development of COPD in Chinese Han population. And the HHIP rs7654947 and FAM13A rs7671167 were associated with lung function decline, and this result was replicated in other two populations.Conclusions: These results suggest an important role of the HHIP and FAM13A regions as genetic risk factors for COPD development and lung function decline in Chinese Han population. Future research on these genes should focus on the molecular mechanisms of these genes on developing COPD and creating therapies to alleviate reduced lung function. [ABSTRACT FROM AUTHOR]