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Mechanisms of CS-related A/J lung tumorigenesis

ABSTRACT: The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening system in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse using transcriptomics and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis illustrated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene signature and show its utility in distinguishing between the cigarette smoke-related and spontaneous lung tumors.

INSTRUMENT(S): Affymetrix GeneChip Scanner 3000 7G

ORGANISM(S): Mus musculus

SUBMITTER: Sam Ansari

PROVIDER: E-MTAB-1871 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mechanisms of CS-related A/J lung tumorigenesis

Project description:The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening system in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse using transcriptomics and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis illustrated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene signature and show its utility in distinguishing between the cigarette smoke-related and spontaneous lung tumors.

2014-08-29 | E-MTAB-1872 | biostudies-arrayexpress

Chronic exposure to waterpipe smoke elicits immunomodulatory and carcinogenic effects in the lung

Project description:Previous reports showed that cigarette smoke exposed normal-appearing airways in phenotypically lung cancer-free smokers carry alterations that are characteristic of tumors – suggestive of an airway field of injury. Very little is known of the effects of the chronic consumption of other forms of tobacco, such as waterpipe smoke (WPS), on lung pathobiology. Here we studied normal-appearing airway brushings from waterpipe smokers and those who were not exposed to WPS. We find that WPS elicits a molecular field of injury with gene programs that are pertinent to lung carcinogenesis.

2022-07-13 | GSE197653 | GEO

Chronic exposure to waterpipe smoke elicits immunomodulatory and carcinogenic effects in the lung II

Project description:Previous reports showed that cigarette smoke elicits various molecular and immune changes in the lung. Very little is known of the effects of the chronic consumption of other forms of tobacco, such as waterpipe smoke (WPS), on lung pathobiology. Here, we studied the effects of chronic exposure to WPS versus control air on lungs of tumor-prone mice by RNA-sequencing (RNA-Seq). We find that WPS elicits immunomodulatory changes in the lung that are pertinent to carcinogenesis.

2022-07-13 | GSE197994 | GEO

Investigating the impact of cigarette smoke on pulmonary cellular immune responses to influenza virus at the single cell resolution in mice.

Project description:Single cell RNA-sequencing (scRNAseq) of lung immune cells from mice exposed to room air or cigarette smoke, infected with influenza A virus. Room air saline controls are also included. This analysis facilitates a comparison of cigarette smoke-associated changes to the pulmonary immune environment at the level of individual leukocytes and stromal cells.

2022-01-03 | GSE186976 | GEO

Dissecting the molecular effects of cigarette smoke on proteasome function

Project description:Proteasome dysfunction is emerging as a novel pathomechanism for the development of chronic obstructive pulmonary disease (COPD), a major leading cause of death in the world. Cigarette smoke is one of the main risk factors for COPD and has been shown to impair proteasome function in vitro and in vivo. Importantly, proteasome activity is inhibited in COPD lungs while expression levels of proteasome subunits are not altered. In the present study, we dissected the molecular changes induced by cigarette smoke on proteasome function in lung epithelial cells and mouse lungs. We analyzed the integrity, composition, and the interactome of isolated 26S proteasome complexes from smoke-exposed cells and mouse lungs. Moreover, we applied native MS analysis to investigate whether reactive compounds of cigarette smoke directly modify and inhibit the 20S proteasome complex. Our data reveal that the 20S proteasome is slightly destabilized in the absence of any dominant modification of proteasomal proteins. 26S pulldown and stoichiometry analysis indicated that 26S proteasome complexes become instable in response to cigarette smoke exposure. Of note, the interactome of the 26S was clearly altered in smoke-exposed mouse lungs possibly reflecting an altered cellular composition in the lungs of the smoke-exposed mice. Taken together, our results suggest that cigarette smoke induces minor but detectable changes in the stability and interactome of 20S and 26S proteasome complexes which might contribute in a chronic setting to imbalanced proteostasis as observed in chronic lung diseases associated with cigarette smoking.

2019-01-08 | PXD007148 | Pride

Comparison analysis of 2 week old C57BL6J lung exposed to 2 weeks of cigarette smoke compared to age-matched controls

Project description:We hypothesize that gene expression in the cigarette smoke (CS) exposed neonatal lung and age-matched controls will be divergent. CS exposed lung will have divergence of immune response genes and structural genes. The lungs of (6) 2 week old neonatal mice exposed to 2 weeks of CS were compared to the lung of (4) 2 week old age-matched control mice. We utilized microarray analysis to examine transcriptional differences between smoke exposed neonatal lung and age-matched controls. Keywords: comparative expression profiling

2008-01-01 | GSE7310 | GEO

Gene expression after 1 and 5 days of cigarette smoke exposure in mice with chronically inflamed or healthy lungs

Project description:These studies tested the hypotheses that smoke induces changes in mRNA profiles that are dependent on sex and the health status of the lung, and that the effects of smoke are different after 1 day compared to 5 days of smoke exposure. The ways in which the lungs modulate their response to cigarette smoke after repeated exposures are important for understanding the toxicology of smoke, for developing biomarkers of chronic smoke exposure, and for understanding the therapeutic potential in regulatory signaling pathways that are beneficial or detrimental to lung health. Sex-matched 5-7-week old wildtype (WT) and Scnn1b-overexpressing (BENaC) littermates were exposed to cigarette smoke or sham (room air) exposure. Exposure occurred in a plexiglass chamber attached to a smoke delivery device using an exposure chamber and smoking machine (inExpose Exposure System, SCIREQ, Chandler, AZ). Mice were exposed to mainstream + sidestream smoke from 6 reference cigarettes with filters removed per day (3R4F research cigarettes, University of Kentucky). Each cigarette was puffed for 2 sec every 25 sec, using the standard Federal Trade Commission smoking machine protocol. The sham-exposed control mice were exposed to room air in the exposure chamber for a time equivalent to that needed for active smoke exposure. Mice were exposed to cigarette or sham smoke for 1 day or 5 consecutive days. Samples were harvested 4 hours after the completion of the final smoke exposure. The right lung was used for gene expression analysis.

2019-03-18 | GSE109776 | GEO

Cigarette smoking prolongs immune responses against influenza and delays its clearance in mice

Project description:Introduction Epidemiological studies have shown that smoking is associated with increased incidence of severe viral infections leading to hospitalisation. Moreover, studies in experimental models have identified impaired antiviral responses and altered inflammatory responses, yet it is unclear which immune cells are involved and whether this varies over the course of infection. Methods To test how cigarette smoking affects the response to influenza viral infection over time, female BALB/c mice were exposed to cigarette smoke or air twice a day for 24-28 days and infected with H3N2 influenza or mock infection on day 21. Three and seven days after infection, changes in immune cell populations, and mRNA expression/viral clearance in lung tissue were analysed. Results Smoke-exposed mice lost significantly more weight than air-exposed controls after influenza infection, indicating that smoking resulted in more severe disease. Immune cell and lung tissue transcriptome analysis revealed that neutrophil infiltration was prolonged and macrophage activation dysregulated after infection in smoke-exposed mice compared to air-exposed controls. Expression of genes in IL-6 and interferon pathways was similarly longer active. In parallel, we observed lower clearance of viral RNA in smoke-exposed mice after infection compared to air-exposed controls, indicating ineffective antiviral responses. Adaptive immune responses were unchanged in infected smoking animals compared to nonsmoking mice. Conclusion Altogether, the data from our mouse model indicate that cigarette smoke exposure prolongs innate immune responses against influenza. The results from this study help to explain the susceptibility of current smokers to severe influenza disease.

2024-06-21 | GSE269227 | GEO

p21-Activated kinase 6 (PAK6) is associated with enhanced proliferation in lung cells exposed chronically to cigarette smoke

Project description:Epidemiological data clearly establishes cigarette smoking as one of the major cause for lung cancer worldwide. There is no standard screening method for lung cancer even in high-risk populations and the overall five-year survival has not changed significantly in the last decade. First-line treatment for lung cancer includes surgical resection, chemotherapy, and radiation. Recently with the advancement of systems biology, targeted therapy has become one of the most preferred modes of treatment for cancer. Though certain targeted therapies such as anti-EGFR are in clinical practice, they have shown limited success in the smokers suffering from lung cancer. This demands the discovery of alternative drug targets through systematic investigation of altered signaling mechanisms. To study dysregulated signaling pathways due to chronic cigarette smzoke exposure, we carried out SILAC-based phosphoproteome analysis of lung cell line H358 chronically exposed to cigarette smoke. We identified 1,812 phosphosites, of which 278 were hyperphosphorylated (≥ 3-fold) in the H358 cells exposed to cigarette smoke. We identified several known and some novel kinases and key signaling molecules that were hyperphosphorylated in response to chronic exposure to cigarette smoke

2016-12-14 | PXD003108 | Pride

Diet-Induced Obesity Exacerbates Inflammatory and Oxidative Stress Responses in Mice Exposed to Cigarette Smoke

Project description:To identify biosignatures that describe these lifestyle susceptibility factors, we performed parallel exposures of regular weight (RW) C57BL/6 and diet-induced obese (DIO) C57BL/6 mice to cigarette smoke, either mainstream (MS) or sidestream (SS), mimicking both the smoker and environmental exposure through second-hand smoke, respectively. Transcriptional responses were measured by global microarray analysis of lung tissue. Groups (N=8 biological replicates) of RW and DIO C57BL/6 mice (15-weeks old at start of exposures) were exposed to either filtered air (sham controls, SC), mainstream (MS) or sidestream (SS) cigarette smoke by nose-only inhalation exposure for 5 hr/day for a total of eight exposures over two weeks as follows: 5 consecutive days of exposure, followed by 2 days with no exposure, then three days of exposure, with necropsies occurring the day following the last exposure.

2012-09-15 | E-GEOD-38093 | biostudies-arrayexpress

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