scholarly journals Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
He Du ◽  
Bi Chen ◽  
Nan-Lin Jiao ◽  
Yan-Hua Liu ◽  
San-Yuan Sun ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glutathione Peroxidase ◽  
Lung Adenocarcinoma ◽  
Cell Line ◽  
A549 Cells ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Lung

The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.

scholarly journals Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yuqing Lou ◽  
Jianlin Xu ◽  
Yanwei Zhang ◽  
Wei Zhang ◽  
Xueyan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Line ◽  
Quantitative Polymerase Chain Reaction ◽  
Mutant Cell ◽  
A549 Cells ◽  
The Cancer Genome Atlas ◽  
Akt Kinase ◽  
Egfr Expression

AbstractEpidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD). Resistance to EGFR tyrosine kinase inhibitors is a major obstacle for EGFR-mutant LUAD patients. Our gene chip array, quantitative polymerase chain reaction validation, and shRNA-based high-content screening identified the Akt kinase lanthionine synthetase C-like protein 2 (LANCL2) as a pro-proliferative gene in the EGFR-mutant LUAD cell line PC9. Therefore, we investigated whether LANCL2 plays a role in promoting cell proliferation and drug resistance in EGFR-mutant LUAD. In silico clinical correlation analysis using the Cancer Genome Atlas Lung Adenocarcinoma dataset revealed a positive correlation between LANCL2 and EGFR expression and an inverse relationship between LANCL2 gain-of-function and survival in LUAD patients. The EGFR-mutant LUAD cell lines PC9 and HCC827 displayed higher LANCL2 expression than the non-EGFR-mutant cell line A549. In addition, LANCL2 was downregulated following gefitinib+pemetrexed combination therapy in PC9 cells. LANCL2 knockdown reduced proliferation and enhanced apoptosis in PC9, HCC827, and A549 cells in vitro and suppressed murine PC9 xenograft tumor growth in vivo. Notably, LANCL2 overexpression rescued these effects and promoted gefitinib + pemetrexed resistance in PC9 and HCC827 cells. Pathway analysis and co-immunoprecipitation followed by mass spectrometry of differentially-expressed genes in LANCL2 knockdown cells revealed enrichment of several cancer signaling pathways. In addition, Filamin A and glutathione S-transferase Mu 3 were identified as two novel protein interactors of LANCL2. In conclusion, LANCL2 promotes tumorigenic proliferation, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on the positive association between LANCL2, EGFR, and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.

scholarly journals KRT6A Promotes EMT and Cancer Stem Cell Transformation in Lung Adenocarcinoma

2020 ◽  
Vol 19 ◽  
pp. 153303382092124
Author(s):  
Bin Yang ◽  
Wei Zhang ◽  
Mengmeng Zhang ◽  
Xuhong Wang ◽  
Shengzu Peng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Lung Adenocarcinoma ◽  
Biological Function ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Normal Lung ◽  
Mesenchymal Transition

Aim: Keratin 6A is a type II cytokeratin which is important in forming nail bed, filiform papillae, the epithelial lining of oral mucosa, and esophagus; recently, keratin 6A was found hyperexpressed in different types of cancer. But, the biological function of keratin 6A in lung adenocarcinoma still remains unclear. Therefore, in current study, we investigated the biological role of keratin 6A in lung adenocarcinoma. Methods: By utilizing The Cancer Genome Atlas database, we investigated the expression profile of keratin 6A and its relationship with other clinical parameters in lung adenocarcinoma. The biological function of keratin 6A in lung adenocarcinoma was also investigated by using A549 and PC-9 lung cancer cell lines in vitro. Results: Our data indicate that, compared with normal lung tissue samples, keratin 6A was hyperexpressed in lung adenocarcinoma. Moreover, keratin 6A hyperexpression was positively correlated with lymph node positive and aggressive tumor T stage. Keratin 6A knockdown inhibited the cell proliferation, migration, and colony formation ability but not cell death in lung adenocarcinoma cells. In addition, we found keratin 6A exerted its phenotype via promoting cancer stem cells (CXCR4high/CD133high) transformation and epithelial–mesenchymal transition. Conclusion: In conclusion, current study suggests that hyperexpressed keratin 6A in lung adenocarcinoma promotes lung cancer proliferation and metastasis via epithelial–mesenchymal transition and cancer stem cells transformation.

scholarly journals Bioinformatics Analysis Combined With Experiments Predicts CENPK as a Potential Prognostic Factor for Lung Adenocarcinoma

2020 ◽  
Author(s):  
Jiayu Ma ◽  
Xiaochuan Chen ◽  
Mingqiang Lin ◽  
Zhiping Wang ◽  
Yahua Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Bioinformatics Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Biological Behavior ◽  
In Vitro Experiments ◽  
Tumor Identification

Abstract BackgroundLung cancer is the most commonly occurring malignant tumor. Identification of novel diagnostic and prognostic biomarkers for lung cancer is a key research imperative. The role of CENPK in cancer is an emerging area of research. However, the role of CENPK in the progression of lung adenocarcinoma (LAC) is not well characterized. MethodsIn this study, we identified centromere protein K (CENPK) as a potential new gene for lung cancer based on bioinformatics analysis. In addition, in vitro experiments, including were performed to verify the function of this gene. We investigated the expression of CENPK in LAC by bioinformatics analyses of datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, differential expression analyses, gene ontology (GO) enrichment, kyoto encyclopedia of genes and genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to evaluate its diagnostic and prognostic relevance. In vitro experiments including immunohistochemistry analysis, western blot analysis, CCK8 assay, Transwell assay, flow cytometry, wound healing assay, which were conducted to evaluate the biological behavior and role of CENPK in lung cancer cells.ResultsWe demonstrated overexpression of CENPK in LAC; in addition, increased expression of CENPK was associated with clinical progression. Moreover, CENPK was found to be an independent risk factor in patients with LAC. Furthermore, we observed activation of CENPK related signaling pathways in patients with LAC. ConclusionsIn summary, our findings indicate a potential role of CENPK in promoting tumor proliferation, invasion, and metastasis and its application as a novel diagnostic and prognostic biomarker of LAC.

scholarly journals The Sulfotransferase SULT1C2 Is Epigenetically Activated and Transcriptionally Induced by Tobacco Exposure and Is Associated with Patient Outcome in Lung Adenocarcinoma

2021 ◽  
Vol 19 (1) ◽  
pp. 416
Author(s):  
Candace Johnson ◽  
Daniel J. Mullen ◽  
Suhaida A. Selamat ◽  
Mihaela Campan ◽  
Ite A. Offringa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Methylation ◽  
Lung Adenocarcinoma ◽  
Binding Site ◽  
Cell Line ◽  
Cigarette Smoke ◽  
Cell Lines ◽  
Normal Lung ◽  
Tobacco Exposure

Lung cancer is the leading cause of cancer-related death. Tobacco exposure is associated with 80–90% of lung cancer cases. The SULT1C2 sulfotransferase modifies xenobiotic compounds to enhance secretion but can also render these compounds carcinogenic. To determine if SULT1C2 contributes to tobacco-related carcinogenesis in the lung, we analyzed the expression and epigenetic state of SULT1C2 in human lung adenocarcinoma (LUAD) samples and in LUAD cell lines exposed to cigarette smoke condensate (CSC). SULT1C2 expression was significantly positively correlated to overall LUAD patient survival in smokers, was elevated in LUAD tumors compared to adjacent non-tumor lung, and was significantly correlated with levels of patient exposure to tobacco smoke. SULT1C2 promoter DNA methylation was inversely correlated with expression in LUAD, and hypomethylation of the SULT1C2 promoter was observed in Asian patients, as compared to Caucasians. In vitro analysis of LUAD cell lines indicates that CSC stimulates expression of SULT1C2 in a dose-dependent and cell-line-specific manner. In vitro methylation of the SULT1C2 promoter significantly decreased transcriptional activity of a reporter plasmid, and SULT1C2 expression was activated by the DNA demethylating agent 5-Aza-2′-deoxycytidine in a cell line in which the SULT1C2 promoter was hypermethylated. An aryl hydrocarbon receptor (AHR) binding site was detected spanning critical methylation sites upstream of SULT1C2. CSC exposure significantly increased AHR binding to this predicted binding site in the SULT1C2 promoter in multiple lung cell lines. Our data suggest that CSC exposure leads to activation of the AHR transcription factor, increased binding to the SULT1C2 promoter, and upregulation of SULT1C2 expression and that this process is inhibited by DNA methylation at the SULT1C2 locus. Additionally, our results suggest that the level of SULT1C2 promoter methylation and gene expression in normal lung varies depending on the race of the patient, which could in part reflect the molecular mechanisms of racial disparities seen in lung cellular responses to cigarette smoke exposure.

scholarly journals In vitro cytotoxic and genotoxic effects of donkey milk on lung cancer and normal cells lines

2019 ◽  
Vol 37 (No. 1) ◽  
pp. 29-35 ◽  
Author(s):  
Cetin Akca ◽  
Ozgur Vatan ◽  
Dilek Yilmaz ◽  
Huzeyfe HURIYET ◽  
Nilüfer Cinkilic ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Micronucleus Test ◽  
A549 Cells ◽  
Tumor Cell Line ◽  
Normal Lung ◽  
Dna Breaks ◽  
Donkey Milk ◽  
Genotoxic Effects

In vitro cytotoxic and genotoxic effects of donkey milk on cancer (A549) and normal (BEAS-2B) lung cell lines were investigated. The XTT and WST-1 tests as well as clonogenic assays were used to evaluate cytotoxicity. The comet assay and micronucleus test were used as genotoxicity endpoints. Donkey milk showed lower cytotoxic effects against normal lung cell line BEAS-2B in comparison to the tumor cell line A549. Genotoxicity experiments revealed dose dependent increases in the frequencies of micronuclei and single stranded DNA breaks in A549 cells whereas no significant damage was observed in BEAS-2B cells. The results indicate that donkey milk has anti-proliferative and genotoxic effects on lung cancer cells at concentrations which are non-toxic to normal lung cells.

scholarly journals Bioinformatics analysis combined with experiments predicts CENPK as a potential prognostic factor for lung adenocarcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiayu Ma ◽  
Xiaochuan Chen ◽  
Mingqiang Lin ◽  
Zhiping Wang ◽  
Yahua Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Bioinformatics Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Biological Behavior ◽  
Tumor Identification

Abstract Background Lung cancer is the most common malignant tumor. Identification of novel diagnostic and prognostic biomarkers for lung cancer is a key research imperative. The role of centromere protein K (CENPK) in cancer is an emerging research hotspot. However, the role of CENPK in the progression of lung adenocarcinoma (LAC) is not well characterized. Methods In this study, we identified CENPK as a potential new gene for lung cancer based on bioinformatics analysis. In addition, in vitro experiments were performed to verify the function of this gene. We investigated the expression of CENPK in LAC by analyses of datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differential expression analyses, gene ontology (GO) enrichment, Kyoto encyclopedia of genes and genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to evaluate the diagnostic and prognostic relevance of CENPK. Then, for evaluating the biological behavior and role of CENPK in lung cancer cells, we did a series of vitro experiments, such as immunohistochemistry analysis, Western blot analysis, CCK8 assay, transwell assay, flow cytometry, and wound healing assay. Results We demonstrated overexpression of CENPK in LAC; in addition, increased expression of CENPK was associated with clinical progression. Moreover, CENPK was found to be an independent risk factor in patients with LAC. Furthermore, we observed activation of CENPK-related signaling pathways in patients with LAC. Conclusions Our findings indicate a potential role of CENPK in promoting tumor proliferation, invasion, and metastasis. It may serve as a novel diagnostic and prognostic biomarker in patients with LAC.

scholarly journals Overexpression of SHMT2 Predicts a Poor Prognosis and Promotes Tumor Cell Growth in Bladder Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Zhang ◽  
Qian Yang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Bladder Cancer ◽  
Disease Free Survival ◽  
Enrichment Analysis ◽  
Tumor Grade ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Bladder

SHMT2 was overexpressed in many tumors, however, the role of SHMT2 in bladder cancer (BLCA) remains unclear. We first analyzed the expression pattern of SHMT2 in BLCA using the TNMplot, Oncomine, the Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases. Next, the association between SHMT2 expression and overall survival (OS)/disease-free survival (DFS) in BLCA patients were analyzed using TCGA and PrognoScan database. The correlation between SHMT2 expression and clinicopathology was determined using TCGA database. Furthermore, the genes co-expressed with SHMT2 and their underlying molecular function in BLCA were explored based on the Oncomine database, Metascape and gene set enrichment analysis (GSEA). Finally, the effects of SHMT2 on cell proliferation, cell cycle, and apoptosis were assessed using in vitro experiments. As a results, SHMT2 was significantly overexpressed in BLCA tissues and cells compared to normal bladder tissues and cells. A high SHMT2 expression predicts a poor OS of BLCA patients. In addition, SHMT2 expression was higher in patients with a high tumor grade and in those who were older than 60 years. However, the expression of SHMT2 was not correlated with gender, tumor stage, lymph node stage, and distant metastasis stage. Finally, overexpression of SHMT2 promoted BLCA cell proliferation and suppressed apoptosis, the silencing of SHMT2 significantly inhibited BLCA cell proliferation by impairing the cell cycle, and promoting apoptosis. SHMT2 mediates BLCA cells growth by regulating STAT3 signaling. In summary, SHMT2 regulates the proliferation, cell cycle and apoptosis of BLCA cells, and may act as a candidate therapeutic target for BLCA.

scholarly journals ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

2020 ◽  
Author(s):  
Hui-er Zhu ◽  
Tao Li ◽  
Shengnan Shi ◽  
De-xiong Chen ◽  
Weiping Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Gene Set Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion

Abstract Background: Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown. Methods: Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studied using cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD. Results: We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation. Conclusions: Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

scholarly journals ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Hui-er Zhu ◽  
Tao Li ◽  
Shengnan Shi ◽  
De-xiong Chen ◽  
Weiping Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Gene Set Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion

Abstract Background Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown. Methods Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studiedusing cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD. Results We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation. Conclusions Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

scholarly journals The LncRNA NEAT1 Accelerates Lung Adenocarcinoma Deterioration and Binds to Mir-193a-3p as a Competitive Endogenous RNA

2018 ◽  
Vol 48 (3) ◽  
pp. 905-918 ◽  
Author(s):  
Dan-dan Xiong ◽  
Zu-yun Li ◽  
Lu Liang ◽  
Rong-quan He ◽  
Fu-chao Ma ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Target Genes ◽  
Biological Effects ◽  
Lung Epithelial Cells ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Normal Lung ◽  
In Vitro Experiments ◽  
Reporter Assay

Background/Aims: Long noncoding RNAs (lncRNAs) contribute to the development of multiple malignant tumors. Here, we focused on the biological function and underlying molecular mechanism of an lncRNA, nuclear-enriched abundant transcript 1 (NEAT1), in lung adenocarcinoma (LUAD). Methods: In vitro experiments were conducted to determine the biological effects of NEAT1 in LUAD cells. A luciferase activity reporter assay was performed to corroborate the interaction between NEAT1 and miR-193a-3p. Data from Gene Expression Omnibus (GEO), Oncomine, The Cancer Genome Atlas (TCGA), and our in-house reverse transcription quantitative PCR (RT-qPCR) were combined to examine the expression of NEAT1 and miR-193a-3p in LUAD. To further explore the regulatory mechanism of NEAT1, we searched for putative target genes of miR-193a-3p from 12 online prediction databases and determined genes positively correlated with NEAT1 as candidate targets. Furthermore, we analyzed the expression of these selected genes using data from TCGA. Results: In vitro experiments showed that knockdown of NEAT1 in LUAD cells markedly restrained cell proliferation, invasion, and migration and stimulated cell apoptosis. The dual-luciferase reporter assay demonstrated that miR-193a-3p directly targeted NEAT1 at its 3’-UTR. We then detected NEAT1 and miR-193a-3p in LUAD cells and normal lung epithelial cells and discovered high expression of NEAT1 and low expression of miR-193a-3p in LUAD cell lines. Simultaneously, the pooled results from the GEO, Oncomine, TCGA, and in-house RT-qPCR showed that the NEAT1 expression increased while the miR-193a-3p expression decreased in LUAD tissues versus normal lung tissues. Furthermore, the USF1 gene was not only upregulated in LUAD, but also positively correlated with NEAT1, suggesting that NEAT1 may function as a ceRNA to sponge miR-193a-3p and abrogate the inhibitory effect of miR-193a-3p on USF1. Conclusions: Our findings indicate that NEAT1 plays important roles in the occurrence and progression of LUAD. It may exert its role by acting as a ceRNA to regulate miR-193a-3p.

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