Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage‐specific gene <scp>G</scp>prc5a

Fujimoto, Junya; Nunomura-Nakamura, Sayuri; Liu, Yihua; Liu, Wenhua; McDowell, Tina L.; Jakubek, Yasminka A.; Ezzeddine, Dalia; Ochieng, Joshua K.; Petersen, Jason L.; Davies, Gareth E.; Fukuoka, Junya; Wistuba, Ignacio I.; Ehli, Erik A.; Fowler, Jerry; Scheet, Paul; Kadara, Humam

doi:10.1002/ijc.30851

Cited by 24 publications

(41 citation statements)

References 56 publications

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“…We also analyzed GPRC5A, a G protein-coupled receptor, as a potential biomarker. GPRC5A is mainly expressed in end bronchiolar epithelium [ 46 , 47 ], and Gprc5a −/− mice are sensitive to silica-induced tumorigenesis [ 48 ] and is downregulated in lung adenocarcinomas [ 49 ]. Furthermore, Gprc5a −/− mice are sensitive to acute lung effects [ 50 ] involving ATX responses [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells

Högberg

Adner

et al. 2020

Part Fibre Toxicol

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Background Respirable crystalline silica causes lung carcinomas and many thousand future cancer cases are expected in e.g. Europe. Critical questions are how silica causes genotoxicity in the respiratory epithelium and if new cases can be avoided by lowered permissible exposure levels. In this study we investigate early DNA damaging effects of low doses of silica particles in respiratory epithelial cells in vitro and in vivo in an effort to understand low-dose carcinogenic effects of silica particles. Results We find DNA damage accumulation already after 5–10 min exposure to low doses (5 μg/cm2) of silica particles (Min-U-Sil 5) in vitro. DNA damage was documented as increased levels of γH2AX, pCHK2, by Comet assay, AIM2 induction, and by increased DNA repair (non-homologous end joining) signaling. The DNA damage response (DDR) was not related to increased ROS levels, but to a NLRP3-dependent mitochondrial depolarization. Particles in contact with the plasma membrane elicited a Ser198 phosphorylation of NLRP3, co-localization of NLRP3 to mitochondria and depolarization. FCCP, a mitochondrial uncoupler, as well as overexpressed NLRP3 mimicked the silica-induced depolarization and the DNA damage response. A single inhalation of 25 μg silica particles gave a similar rapid DDR in mouse lung. Biomarkers (CC10 and GPRC5A) indicated an involvement of respiratory epithelial cells. Conclusions Our findings demonstrate a novel mode of action (MOA) for silica-induced DNA damage and mutagenic double strand breaks in airway epithelial cells. This MOA seems independent of particle uptake and of an involvement of macrophages. Our study might help defining models for estimating exposure levels without DNA damaging effects.

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Section: Resultsmentioning

confidence: 99%

Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells

Högberg

Adner

et al. 2020

Part Fibre Toxicol

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“…Lung adenocarcinoma is the most common pathological subtype and it has been widely detected over the years via unique genetic changes and various prognostic factors ( 24 – 26 ). Due to unknown pathogenesis, the mortality of LUAD patients is still high and the treatment outcome is also unsatisfactory ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

A Seven Immune-Related lncRNAs Model to Increase the Predicted Value of Lung Adenocarcinoma

Liu

et al. 2020

Front. Oncol.

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Background Recent research has shown that immune-related lncRNA plays a crucial part in the tumor immune microenvironment. This study tried to identify immune-related lncRNAs and construct a robust prediction model to increase the predicted value of lung adenocarcinoma (LUAD). Methods RNA expression data of LUAD were download from the Cancer Genome Atlas (TCGA) database. Immune genes were acquired from the Molecular Signatures Database (MSigDB). The immune gene related lncRNAs were acquired by the “limma R” package and Cytoscape3.7.1. Cox regression analysis was applied to construct this forecast model. The prognostic model was validated by the testing cohort which was acquired by the bootstrap method. Results A total of 551 lncRNA expression profiles including 497 LUAD tissues and 54 non-LUAD tissues were obtained. A total of 331 immune genes were acquired. The result of the Cox regression analysis showed that seven lncRNAs (AC022784-1, NKILA, AC026355-1, AC068338-3, LINC01843, SYNPR-AS1, and AC123595-1) can be performed to construct the prediction model to forecast the prognosis of LUAD. Kaplan–Meier curves indicated that our prediction model can distribute LUAD patients into two different risk groups (high and low) with significant statistical significance ( P = 1.484e-07). Cox analysis and independent analysis illustrated that the seven-lncRNAs prediction model was an isolated factor by comparing it with other clinical variables. We validated the accuracy of our model in the testing dataset. Furthermore, the prognostic model also showed higher predictive efficiency than three other published prognostic models. The two different survival groups represented diverse immune features according to principal components analysis. GSEA analysis (gene set enrichment analysis) indicated that seven-lncRNAs signatures may be involved in the progression of tumorigenesis. Conclusions We have established a seven immune-related lncRNAs prediction model. This prognostic model had significant clinical significance that increased the predicted value and guided the personalized treatment for LUAD patients.

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“…Adenocarcinoma is the most prevalent histological subtype of lung cancer and has been broadly explored for distinct genetic drivers and diverse prognostic factors. However, LUAD patients still experience high mortality due to undetected pathogenesis [29][30][31]. Many researchers believe that the existing guidelines and definitions of lung cancer may result in different clinical decisions for preoperative and postoperative patients.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a survival model for lung adenocarcinoma based on autophagy-associated genes

Wang¹,

Yao²,

Xiao³

et al. 2020

J Transl Med

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Background: Given that abnormal autophagy is involved in the pathogenesis of cancers, we sought to explore the potential value of autophagy-associated genes in lung adenocarcinoma (LUAD). Methods:RNA sequencing and clinical data on tumour and normal samples were acquired from The Cancer Genome Atlas (TCGA) database and randomly assigned to training and testing groups. Differentially expressed autophagy-associated genes (AAGs) were screened. Within the training group, Cox regression and Lasso regression analyses were conducted to screen five prognostic AAGs, which were used to develop a model. Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were plotted to determine the performance of the model in both groups. Immunohistochemistry was used to demonstrate the differential expression of AAGs in tumour and normal tissues at the protein level. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were utilized to further elucidate the roles of AAGs in LUAD. Results:The data from the TCGA database included 497 tumour and 54 normal samples, within which 30 differentially expressed AAGs were screened. Using Cox regression and Lasso regression analyses for the training group, 5 prognostic AAGs were identified and the prognostic model was constructed. Patients with low risk had better overall survival (OS) in the training group (3-year OS, 73.0% vs 48.0%; 5-year OS, 45.0% vs 33.8%; P = 1.305E−04) and in the testing group (3-year OS, 66.8% vs 41.2%; 5-year OS, 31.7% vs 25.8%; P = 1.027E−03). The areas under the ROC curves (AUC) were significant for both the training and testing groups (3-year AUC, 0.810 vs 0.894; 5-year AUC, 0.792 vs 0.749). Conclusions:We developed a survival model for LUAD and validated the performance of the model, which may provide superior outcomes for the patients.

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Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage‐specific gene Gprc5a

Cited by 24 publications

References 56 publications

Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells

Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells

A Seven Immune-Related lncRNAs Model to Increase the Predicted Value of Lung Adenocarcinoma

Development and validation of a survival model for lung adenocarcinoma based on autophagy-associated genes

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