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Aberrant expression of the zinc finger protein (ZIC) family has been extensively reported to contribute to progression and metastasis in multiple human cancers. However, the functional roles and underlying mechanisms of ZIC2 in non-small cell lung cancer (NSCLC) are largely unknown. In this study, ZIC2 expression was evaluated using qRT-PCR, western blot, and immunohistochemistry, respectively. Animal experiments in vivo and functional assays in vitro were performed to investigate the role of ZIC2 in NSCLC. Luciferase assays and chromatin immunoprecipitation (ChIP) were carried out to explore the underlying target involved in the roles of ZIC2 in NSCLC. Here, we reported that ZIC2 was upregulated in NSCLC tissues, and high expression of ZIC2 predicted worse overall and progression-free survival of NSCLC patients. Silencing ZIC2 repressed tumorigenesis and reduced the anoikis resistance of NSCLC cells. Mechanical investigation further revealed that silencing ZIC2 transcriptionally inhibited Src expression and inactivated steroid receptor coactivator/focal adhesion kinase signaling, which further attenuated the anoikis resistance of NSCLC cells. Importantly, our results showed that the number of circulating tumor cells (CTCs) was positively correlated with ZIC2 expression in NSCLC patients. Collectively, our findings unravel a novel mechanism implicating ZIC2 in NSCLC, which will facilitate the development of anti-tumor strategies in NSCLC., Graphical abstract, We pinpointed the oncogenic role of ZIC2 in NSCLC. Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung carcinoma cells (NSCLCs) by transcriptionally inhibiting Src/FAK signaling. Summarily, ZIC2 may hold the potential biomarker for early diagnosis and anti-tumor strategy in NSCLC.

Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS-CoV-2 pathogenesis remains unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age, and cigarette smoke (CS), in a CS-exposed mouse model and 224 non-malignant lung tissues (125 non-smokers, 81 current smokers, and 18 ex-smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS-induced oxidative stress-related markers, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), and 4-hydroxynonenal (4-HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS-exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex-smokers compared with current smokers, especially in those who had ceased smoking for more than 10 years. Moreover, ACE2 expression was positively correlated with the levels of HIF-1α, iNOS, and 4-HNE in both mouse and human bronchioles. The results were further validated using a publicly available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus 2.0 microarray (AE-meta). Finally, our results showed that HIF-1α transcriptionally upregulates ACE2 expression. Our results indicate that smoking-induced ACE2 overexpression in the apical surface of bronchial epithelial cells provides a route by which SARS-CoV-2 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID-19 in smoking populations by smoking cessation. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Lung cancer is a common malignant tumour and the leading cause of cancer death. Smoking is closely related to lung cancer, which can not only induce the occurrence of lung cancer but also affect its progress and prognosis. Objectives To investigated the relationship between smoking and 14-3-3σ protein expression in non-small-cell lung cancer (NSCLC), investigated the relationship between 14-3-3σ expression and cell migration in A549 cells induced by cigarette smoke extract (CSE) and explored whether DNA methylation plays a role in the decreased expression of 14-3-3σ induced by CSE. Methods 14-3-3σ protein expression was examined by immunohistochemistry in 152 NSCLC tissue samples. In vitro experiments were divided into three groups: The current smoking group (CS), the ex-smoking group (ES) and the normal control group (NC). Cell transfection was used for 14-3-3σ protein overexpression. The mRNA and protein expression levels of 14-3-3σ were detected by RT-PCR and Western blotting, respectively. Cell migration was detected by Transwell and wound-healing assays, and the methylation of 14-3-3σ was detected by methylation-specific PCR. Results 14-3-3σ protein expression was decreased in NSCLC patients with a history of smoking. The expression of 14-3-3σ was decreased in A549 cells treated with CSE. The migration capacity of A549 cells treated with CSE was enhanced. DNA methylation in the cigarette smoke-treated A549 cells was higher than that in the untreated cells. Conclusion Cigarette smoke induced reduction of 14-3-3σ expression can promote the progression of non-small cell lung cancer.

Neutrophil extracellular traps (NETs) were initially identified as an important antimicrobial barrier to capture and kill microorganisms. Emerging evidence suggests that NETs play a crucial role in chronic airway inflammation induced by cigarette smoke (CS). However, how NETs form and the mechanisms by which NETs function in CS-related airway diseases are still unclear. To explore NET formation and its potential role in CS-related airway diseases, we first established a CS-induced subacute airway inflammation model in mice and verified NET formation in the airways. Moreover, NETs degradation by aerosolized DNase I treatment significantly inhibited the airway inflammation induced by CS in mice. More importantly, by in vitro experiments, we found that cigarette smoke extract (CSE) induces NET formation in an NADPH oxidase-dependent manner, and that macrophages and human bronchial epithelial cells (HBEs) are important targets for the NETs-induced secretion of inflammatory cytokines. Therefore, NETs may represent a critical link among neutrophils, macrophages and HBEs under chronic inflammation conditions induced by CS.