Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling

Chen, Jia‐Rong; Liu, Aibin; Lin, Zhichao; Wang, Bin; Chai, Xingxing; Chen, Shasha; Lu, Wenjie; Zheng, Mingzhu; Cao, Ting; Zhong, Meigong; Li, Ronggang; Wu, Mingyan; Lu, Zhuming; Pang, Wei; Huang, Wenhai; Lin, Xiao; Lin, Dongdong; Wang, Zhihui; Lei, Fangyong; Chen, Xiangmeng; Long, Wansheng; Zheng, Yan; Chen, Qiong; Zeng, Jincheng; Ren, Dong; Li, Jun; Zhang, Xin; Huang, Yanming

doi:10.1016/j.canlet.2020.04.007

Cited by 61 publications

(54 citation statements)

References 47 publications

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“…Therefore, PPAR cannot be completely silenced in Fmo5 −/− mice. PPARα is a key gene in the PPAR signaling pathway, which plays a role in cellular lipids by regulating the expression of genes involved in lipid metabolism in the liver [22,23]. PPARα gene knockout promotes inflammation and aggravates lipid deposition in the liver.…”

Section: Discussionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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“…IHC was performed using anti-CD31 Monoclonal Antibody (Cell Signal Technology, USA). The number of tumor cell per mm 2 was calculated as previous described [28]. Briefly, the tumor cell number was evaluated in 9 random fields (mm 2 ) of the H&E tissues under 20X magnification using Precipoint M8 Digital Microscopy (Germany).…”

Section: Animal Studymentioning

confidence: 99%

LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression

et al. 2020

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Background Anti-angiogenic therapy represents a promising strategy for non-small-cell lung cancer (NSCLC) but its application in lung squamous cell carcinoma (SQC) is limited due to the high-risk adverse effects. Accumulating evidence indicates that long noncoding RNAs (lncRNAs) mediate in tumor progression by participating in the regulation of VEGF in NSCLC, which might guide the development of new antiangiogenic strategies. Methods Differential lncRNA expression in SQC was analyzed in AE-meta and TCGA datasets, and further confirmed in lung cancer tissues and adjacent normal tissues with RT-qPCR and in-situ hybridization. Statistical analysis was performed to evaluate the clinical correlation between LINC00173.v1 expression and survival characteristics. A tube formation assay, chick embryo chorioallantoic membrane assay and animal experiments were conducted to detect the effect of LINC00173.v1 on the proliferation and migration of vascular endothelial cells and tumorigenesis of SQC in vivo. Bioinformatics analysis, RNA immunoprecipitation and luciferase reporter assays were performed to elucidate the downstream target of LINC00173.v1. The therapeutic efficacy of antisense oligonucleotide (ASO) against LINC00173.v1 was further investigated in vivo. Chromatin immunoprecipitation and high throughput data processing and visualization were performed to identify the cause of LINC00173.v1 overexpression in SQC. Results LINC00173.v1 was specifically upregulated in SQC tissues, which predicted poorer overall and progression-free survival in SQC patients. Overexpression of LINC00173.v1 promoted, while silencing LINC00173.v1 inhibited the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells in vitro and in vivo. Our results further revealed that LINC00173.v1 promoted the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells by upregulating VEGFA expression by sponging miR-511-5p. Importantly, inhibition of LINC00173.v1 via the ASO strategy reduced the tumor growth of SQC cells, and enhanced the therapeutic sensitivity of SQC cells to cisplatin in vivo. Moreover, our results showed that squamous cell carcinoma-specific factor ΔNp63α contributed to LINC00173.v1 overexpression in SQC. Conclusion Our findings clarify the underlying mechanism by which LINC00173.v1 promotes the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC, demonstrating that LINC00173.v1-targeted drug in combination with cisplatin may serve as a rational regimen against SQC.

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“…Human lung tissues were stained with cell typespecific markers: surfactant protein C (SFTPC, ATII cell marker, 10774-1-AP, 1:1600 dilution; Proteintech, Wuhan, Hubei, PR China); CD68 (pulmonary alveolar macrophage marker, 28058-1-AP, 1: 1500 dilution; Proteintech); CC10 (club cell marker, 10490-1-AP, 1:400 dilution; Proteintech); and Ac-α-tubulin (ciliated cell marker, ab179484, 1:2000 dilution; Abcam). The IHC procedures and expression scoring were as described previously [24,25]. Two experienced independent investigators blindly determined the staining index (SI); these indexes were averaged for further comparative evaluation of ACE2 expression.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

Overexpression of the SARS‐CoV‐2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia

Liu

Zhang

et al. 2020

The Journal of Pathology

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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 remain 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 public available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus2.0 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 provide 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. This article is protected by copyright. All rights reserved.

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Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling

Cited by 61 publications

References 47 publications

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression

Overexpression of the SARS‐CoV‐2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia

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