Altered Cell-Cycle Control, Inflammation and Adhesion in High-Risk Persistent Bronchial Dysplasia
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ABSTRACT:
PROVIDER: PRJNA471529 | ENA |
REPOSITORIES: ENA
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Project description:Persistent bronchial dysplasia (BD) is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. We hypothesized that differences in gene expression profiles between persistent and regressive BD would identify cellular processes that underlie progression to SCC. RNA expression arrays (Affymetrix Hu 1.0) comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes (ANOVA, FDR</=0.05). Thirty-one pathways showed statistically significant evidence of altered activity between the two groups. Multiple pathways were associated with cell cycle control/proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Polo-like kinase 1 (PLK1) was associated with multiple cell cycle pathways. Cultured persistent BD cells showed increased PLK1 expression, and following treatment with PLK1 inhibitor, showed induction of apoptosis, G2/M phase arrest and decreased proliferation compared to untreated cells. These effects were not seen in normal or regressive BD cultures. Inflammatory pathway activity was decreased in persistent BD and the presence of an inflammatory infiltrate was more common in regressive BD. Regressive BDs were also associated with trends toward overall increases in macrophages and T-lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of BD. The results identify alterations in cell cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion in the persistent subset of BDs that are associated with high risk for progression to invasive SCC. These pathways may provide strong markers of risk and effective targets for lung cancer prevention.
2018-05-16 | GSE114489 | GEO
Project description:Persistent bronchial dysplasia is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. In this study, we hypothesized that differences in gene expression profiles between persistent and regressive bronchial dysplasia would identify cellular processes that underlie progression to SCC. RNA expression arrays comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes [ANOVA, FDR ? 0.05). Thirty-one pathways showed significantly altered activity between the two groups, many of which were associated with cell-cycle control and proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Cultured persistent bronchial dysplasia cells exhibited increased expression of Polo-like kinase 1 (PLK1), which was associated with multiple cell-cycle pathways. Treatment with PLK1 inhibitor induced apoptosis and G2-M arrest and decreased proliferation compared with untreated cells; these effects were not seen in normal or regressive bronchial dysplasia cultures. Inflammatory pathway activity was decreased in persistent bronchial dysplasia, and the presence of an inflammatory infiltrate was more common in regressive bronchial dysplasia. Regressive bronchial dysplasia was also associated with trends toward overall increases in macrophages and T lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of bronchial dysplasia. These results identify alterations in the persistent subset of bronchial dysplasia that are associated with high risk for progression to invasive SCC. These alterations may serve as strong markers of risk and as effective targets for lung cancer prevention.Significance: Gene expression profiling of high-risk persistent bronchial dysplasia reveals changes in cell-cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion that may underlie progression to invasive SCC. Cancer Res; 78(17); 4971-83. ©2018 AACR.
| S-EPMC6147150 | biostudies-literature
Project description:Insufficient activation of the TGF-b signaling pathway leads to abnormalities in embryonic lung development. Herein, we determined the effect of the epithelial over-activation of the TGF-b signaling pathway in the embryonic lung development by expressing the constitutive active form of the Tgf-b receptor 1. Ectopic activation of the TGF-b signaling pathway in the lung embryonic epithelium resulted in a complex and lethal phenotype in male mice, but not in female mice. Mutant male embryos died at birth due to their inability to breathe, and showed a bronchial-pulmonary-dysplasia-like phenotype which included reduced lung size, increased alveolar wall thickness, increased cellular density of the lung parenchyma and diminished population of club cells. While the NOTCH signaling, pathway was not affected, we found that protein expression of the endodermal stem cell marker Ssea1 was strongly reduced in proximal lung airways of male lungs. In the distal lung epithelium, ectopic activation of the TGF-b signaling pathway resulted in the increased number of Sox9+ alveolar progenitor cells. Moreover, deletion of one Sox9 allele reduced the severity of the phenotype in mutant males, suggesting that TGF-b mediated over-expression of Sox9 protein is critical for the development of the bronchial pulmonary dysplasia-like phenotype displayed by the mutant male animals. Gene expression profiling identified 993 differentially expressed genes in the mutant male lungs compared to the control male lung. Several of these genes, such as Cbr2 and Hp, are expressed by the club cell and were downregulated by the TGF-b signaling pathway in the mutant male lung. Others such as Spock2, Adamtsl2 and Adamts18 were previous found to be linked to fetal lung disease and indispensable for proper lung development. Finally, we showed that injection of b-estradiol in the pregnant female rescued the phenotype in the mutant male embryos which suggests a critical role of the sex hormones in the pathogenesis of the bronchial pulmonary dysplasia disease. In conclusion, we have established a novel sex-specific mouse model that may be helpful in elucidating specific pathways by which sex adversely affects the well-known but obscure more adverse outcome of male patients.
2019-04-11 | GSE97789 | GEO
Project description:Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the relationship between expression imbalance of adhesion molecules and asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray. The results showed that there were various adhesion molecules with abnormal expressions in peripheral blood leucocytes of asthma patients.
2014-02-01 | GSE54605 | GEO
Project description:The study focus was differential methylation in bronchial biopsies between persistent asthma, asthma in remission and healthy controls using Illumina 450k arrays.
| EGAS00001003739 | EGA
Project description:The study focus was differential expression in bronchial biopsies between persistent asthma, asthma in remission and healthy controls using RNAseq.
| EGAS00001003735 | EGA
Project description:Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the relationship between expression imbalance of adhesion molecules and asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray. The results showed that there were various adhesion molecules with abnormal expressions in peripheral blood leucocytes of asthma patients. RNA was extracted from leucocytes in peripheral blood of 4 normal adults and 6 asthma patients by using TRIzol Reagent. Microarray expression studies were performed using the GEArray Q Series Human Extracellular Matrix & Adhesion Molecules Gene Array (SABiosciences Corporation, USA). This microarray profiles the expression of 96 genes key to the functions of cell adhesion. A negative control (PUC18DNA and blank), and the housekeeping genes including β-actin, GAPDH, Cyclophilin A and ribose body protein L13a were spread on each chip.
2014-02-01 | E-GEOD-54605 | biostudies-arrayexpress
Project description:Biological mechanisms explaining asthma control improvement following bronchial thermoplasty are still not well understood. We used a large-scale transcriptomic approach to evaluate the transcriptome of bronchial epithelial cell (BEC) obtained before and after bronchial thermoplasty treatment (BT).
2023-11-29 | GSE216617 | GEO
Project description:Microbiome features of bronchopulmonary dysplasia
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Project description:human bronchial epithelial culture
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