DNA repair and genomic stability in lungs affected by acute injury

Sergio, Luiz Philippe da Silva; Mencalha, André Luiz; Fonseca, Adenilson de Souza da; Paoli, Flávia de

doi:10.1016/j.biopha.2019.109412

Cited by 7 publications

(8 citation statements)

References 145 publications

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“…These alterations can lead to treatment resistance by promoting the transdifferentiation of LUAD to squamous cell carcinoma ( 36 , 37 ). However, ROS directly cause cell injury, including DNA damage ( 38 , 39 ). Cancer cells must counteract excessive oxidative damage for survival ( 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

MRPL51 is a downstream target of FOXM1 in promoting the malignant behaviors of lung adenocarcinoma

Zhang

et al. 2023

Oncol Lett

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Mitochondrial ribosome protein L51 (MRPL51) is a 39S subunit protein of the mitochondrial ribosome. Its dysregulation may be involved in non-small cell lung cancer. The present study aimed to explore MRPL51 expression in lung adenocarcinoma (LUAD) and normal lung tissues, as well as its regulatory effects on malignant LUAD behaviors. In addition, the role of forkhead box protein M1 (FOXM1) in MRPL51 transcription was studied. Bioinformatics analysis and subsequent in vitro experiments, including western blotting, immunofluorescent staining, Transwell invasion assay, dual-luciferase assay and chromatin immunoprecipitation quantitative PCR were conducted. The results demonstrated that MRPL51 expression was upregulated at both the mRNA and protein levels in LUAD tissues compared with normal lung tissues. Gene Set Enrichment Analysis demonstrated that LUAD tissues with higher MRPL51 expression also had higher expression levels of genes enriched in multiple gene sets, including ‘DNA_REPAIR’, ‘UNFOLDED_PROTEIN_RESPONSE’, ‘MYC_TARGETS_V1’, ‘OXIDATIVE_ PHOSPHORYLATION’, ‘MTORC1_SIGNALING’, ‘REACTIVE_OXYGEN_SPECIES_PATHWAY’, ‘MYC_ TARGETS_V2’, ‘E2F_TARGETS’ and ‘G2M_ CHECKPOINT’. MRPL51 expression was positively correlated with ‘cell cycle’, ‘DNA damage’, ‘DNA repair’, epithelial-mesenchymal transition (‘EMT’), ‘invasion’ and ‘proliferation’ of LUAD cells at the single-cell level. Compared to the negative control, MRPL51 knockdown decreased N-cadherin and vimentin expression but increased E-cadherin expression in A549 and Calu-3 cells. MRPL51 knockdown suppressed cell proliferation, induced G1 phase arrest and decreased cell invasion. Patients with LUAD and higher MRPL51 expression had a significantly shorter overall survival (OS). FOXM1 could bind to the MRPL51 gene promoter and activate its transcription. In conclusion, MRPL51 was transcriptionally activated by FOXM1 in LUAD and contributed to the malignant behaviors of tumor cells, including EMT, cell cycle progression and invasion. High MRPL51 expression may be a prognostic biomarker indicating poor OS.

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Section: Discussionmentioning

confidence: 99%

MRPL51 is a downstream target of FOXM1 in promoting the malignant behaviors of lung adenocarcinoma

Zhang

et al. 2023

Oncol Lett

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“…Recent studies have reported that TOP2α, as the encoded protein of TOP2A, is the cause of genomic DNA damage [ 29 , 30 ]. Interestingly, DNA damage and repair process has been implicated in a variety of pulmonary diseases, including acute lung injury [ 31 , 32 ]. Since Type II DNA topoisomerase can induce spontaneous double-strand break in genome [ 29 ], our data suggest that TOP2A mediated DNA damage response may be involved in the development of sepsis-induced ARDS, which required further experimental validation.…”

Section: Discussionmentioning

confidence: 99%

Predicting candidate therapeutic drugs for sepsis-induced acute respiratory distress syndrome based on transcriptome profiling

et al. 2021

Bioengineered

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Sepsis-induced acute respiratory distress syndrome (ARDS) remains a major threat to human health without effective therapeutic drugs. Previous studies demonstrated the power of gene expression profiling to reveal pathological changes associated with sepsis-induced ARDS. However, there is still a lack of systematic data mining framework for identifying potential targets for treatment. In this study, we demonstrated the feasibility of druggable targets prediction based on gene expression data. Through the functional enrichment analysis of microarray-based expression profiles between sepsis-induced ARDS and non-sepsis ARDS samples, we revealed genes involved in anti-microbial infection immunity were significantly altered in sepsis-induced ARDS. Protein-protein interaction (PPI) network analysis highlighted TOP2A gene as the key regulator in the dysregulated gene network of sepsis-induced ARDS. We were also able to predict several therapeutic drug candidates for sepsis-induced ARDS using Connectivity Map (Cmap) database, among which doxorubicin was identified to interact with TOP2A with a high affinity similar to its endogenous ligand. Overall, our findings suggest that doxorubicin could be a potential therapeutic for sepsis-induced ARDS by targeting TOP2A, which requires further investigation and validation. The whole study relies on publicly available dataset and publicly accessible database or bioinformatic tools for data mining. Therefore, our study benchmarks a workflow for druggable target prediction which can be widely applicable in the search of targets in other pathological conditions.

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“…We speculated that the genomic stability was disrupted by the unbalanced cellular environment and metabolic stress in the early stage of JSRV infection [34]. Metabolic stress leaded to a large accumulation of misfolded proteins, produced excessive ROS and damaged organelles which further infected DNA synthesis and repair [35]. Tumor cells were filled in lung tissues which leaded to hypoxia when OPA tumor formed [36].…”

Section: Discussionmentioning

confidence: 99%

Interaction between envelope protein of Jaagsiekte Sheep Retrovirus and Hippo signaling pathway is inferred from transcriptome analysis of naturally infected Ovine Pulmonary Adenomatosis

Duan

Yang

Zhang

et al. 2021

Preprint

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Background Ovine pulmonary adenomatosis (OPA) is a contagious lung epithelial tumor of sheep caused by jaagsiekte sheep retrovirus (JSRV), which causes severe economic losses for the sheep industry in the world. The specific oncogenic mechanism of JSRV is not yet clarified. Methods In this study, RNA was extracted from lung tissues of 3 naturally infected OPA cases and 3 healthy individuals for transcriptome sequencing (RNA-Seq). Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm the sequencing data. Immunohistochemistry (IHC) and western blot (WB) were performed to confirm the signaling pathway enriched by DEGs that was activated in naturally infected OPA cases. Cell viability, wound-healing, transwell and colony formation assays were performed to assess the cell malignant transformation of sheep trophoblast cells (STCs) transformed with JSRV- env lentivirus in vitro, and then WB was performed to confirm the signaling pathway that had been validated in the lung tissues. Results A total of 366 DEGs (154 up-regulated and 212 down-regulated) were identified by RNA-Seq of lung tissues of naturally infected OPA cases and healthy individuals. GO analysis showed that 366 DEGs were significantly enriched in 178 GO terms, including 114 biological processes, 19 cellular components and 45 molecular functions. KEGG analysis showed that the DEGs mainly enriched in cell proliferation, differentiation, apoptosis and migration, such as PI3K/Akt/mTOR, MAPK and Hippo signaling pathway, and Hippo signaling pathway has never been reported in naturally infected OPA cases. qRT-PCR results of 10 DEGs which were selected randomly were consistent with RNA-Seq results. The protein expression of Hippo signaling pathway were up-regulated in naturally infected OPA lung tissues. Cell viability, wound-healing, transwell and colony formation assays confirmed that JSRV- env lentivirus caused malignant transformation of STCs and JSRV Env increased the protein expression of Hippo signaling pathway. Conclusions This research first identified the changes in the transcriptome level of naturally infected OPA lung tissues. These data confirm that the Hippo signaling pathway is involved in the mechanism of OPA, clarify the interaction between Hippo signaling pathway and JSRV Env, provide further evidence for the tumorigenic mechanism of JSRV.

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DNA repair and genomic stability in lungs affected by acute injury

Cited by 7 publications

References 145 publications

MRPL51 is a downstream target of FOXM1 in promoting the malignant behaviors of lung adenocarcinoma

MRPL51 is a downstream target of FOXM1 in promoting the malignant behaviors of lung adenocarcinoma

Predicting candidate therapeutic drugs for sepsis-induced acute respiratory distress syndrome based on transcriptome profiling

Interaction between envelope protein of Jaagsiekte Sheep Retrovirus and Hippo signaling pathway is inferred from transcriptome analysis of naturally infected Ovine Pulmonary Adenomatosis

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