Screening of Hub Genes Associated with Pulmonary Arterial Hypertension by Integrated Bioinformatic Analysis

Zeng, Yu; Li, Nanhong; Zheng, Zhenzhen; Chen, Riken; Peng, Min; Liu, Wang; Zhu, Jiang; Zeng, Mingqing; Cheng, Junfen; Hong, Cheng

doi:10.1155/2021/6626094

Cited by 14 publications

(8 citation statements)

References 67 publications

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“…Significantly elevated N-cad, FN1, and VEGF may contribute to increased potential of FZD9 -/- adenomas for progression to carcinoma ( Figure 5A ). Increased COL1a2 may result from the presence of cancer associated fibroblasts in FZD9 -/- adenomas and is associated with poor prognosis ( 22 ). ESR1 is overexpressed in NSCLC and promotes proliferation, migration, and invasion of lung cancer cells ( 23 ).…”

Section: Resultsmentioning

confidence: 99%

Loss of Frizzled 9 in Lung Cells Alters Epithelial Phenotype and Promotes Premalignant Lesion Development

et al. 2022

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The transmembrane receptor Frizzled 9 (FZD9) is important for fetal neurologic and bone development through both canonical and non-canonical WNT/FZD signaling. In the adult lung, however, Fzd9 helps to maintain a normal epithelium by signaling through peroxisome proliferator activated receptor γ (PPARγ). The effect of FZD9 loss on normal lung epithelial cells and regulators of its expression in the lung are unknown. We knocked down FZD9 in human bronchial epithelial cell (HBEC) lines and found that downstream EMT targets and PPARγ activity are altered. We used a FZD9-/- mouse in the urethane lung adenocarcinoma model and found FZD9-/- adenomas had more proliferation, increased EMT signaling, decreased activation of PPARγ, increased expression of lung cancer associated genes, increased transformed growth, and increased potential for invasive behavior. We identified PPARγ as a transcriptional regulator of FZD9. We also demonstrated that extended cigarette smoke exposure in HBEC leads to decreased FZD9 expression, decreased activation of PPARγ, and increased transformed growth, and found that higher exposure to cigarette smoke in human lungs leads to decreased FZD9 expression. These results provide evidence for the role of FZD9 in lung epithelial maintenance and in smoking related malignant transformation. We identified the first transcriptional regulator of FZD9 in the lung and found FZD9 negative lesions are more dangerous. Loss of FZD9 creates a permissive environment for development of premalignant lung lesions, making it a potential target for intervention.

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Section: Resultsmentioning

confidence: 99%

Loss of Frizzled 9 in Lung Cells Alters Epithelial Phenotype and Promotes Premalignant Lesion Development

et al. 2022

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“…SPP1 gene was also identi ed as a hub gene for PAH by a previous comprehensive gene expression analysis, which veri es our ndings [23; 24 ]. The role of the SPP1 gene in the proliferation of pulmonary vascular smooth muscle cells (PVSMCs) has previously been demonstrated [24]. The increase in the expression of the SPP1 gene in PAH has also been shown [25].…”

Section: Discussionmentioning

confidence: 98%

“…SPP1 was also identi ed as a hub gene for idiopathic pulmonary arterial hypertension (IPAH) [22]. Previous studies showed that CCL5 was also identi ed as hub genes in PAH [24]. CCL5 has been proven to have a signi cant function in pulmonary vascular remodeling in the past.…”

Section: Discussionmentioning

confidence: 99%

In Silico Analysis of Pulmonary Arterial Hypertension to İdentify Key Biomarkers at Protein and RNA Levels

Akçay

2022

Preprint

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Background Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder marked by a raised hypertension in the pulmonary arteries. There is no remedy for PAH, existing medications can help to reduce the disease’s progression. The goal of this research was to investigate potential protein and RNA biomarkers of PAH by bioinformatic analysis. Methods Two PAH datasets accessed from the publicly available Gene Expression Omnibus (GEO) database were utilized to discover differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for common DEGs were conducted by the DAVID tool. Cytoscape was used to create the protein-protein interaction (PPI) and pick the top 10 hub genes. The transcription factors (TFs) and microRNAs (miRNAs) that target DEGs and hub genes were investigated using the JASPAR database. Potential therapeutics that target the top hub genes have been discovered. Results Ten hub genes were discovered to be linked to the pathogenesis of PAH (CCL5, TLR4, TLR1, SPP1, CYBB, HGF, IGF1, SELL, CD163 and POSTN). “Positive regulation of tumor necrosis factor biosynthetic process” and a “toll-like receptor signaling pathway” are the most enriched GO term and KEGG pathway, respectively. “hsa-mir-26b-5p, hsa-mir-146a-5p, hsa-mir-335-5p” and FOXC1, YY1, GATA2 are the top TFs targeting hub genes. 21 drugs targeting ten hub genes have been discovered. Conclusions Our results would help to discover the pathogenesis of PAH and hub genes, miRNAs and 10 TFs that might serve as potential therapeutic targets at protein and RNA levels for PAH patients.

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“…Growing evidence suggested that lncRNAs and circRNAs with miRNA binding sites (MREs) could compete with mRNAs for binding to miRNAs, thereby regulating the RNA expression and affecting disease progression. Despite several ceRNA networks and lncRNA-miRNA interactions have been reported in the lung tissue of HPH [ 37 – 39 ], the crosstalk of lncRNA/circRNA-miRNA-mRNA in the pulmonary arteries of HPH rats has never been investigated.…”

Section: Discussionmentioning

confidence: 99%

Decoding ceRNA regulatory network in the pulmonary artery of hypoxia-induced pulmonary hypertension (HPH) rat model

et al. 2022

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Background Hypoxia-induced pulmonary hypertension (HPH) is a lethal cardiovascular disease with the characteristic of severe remodeling of pulmonary vascular. Although a large number of dysregulated mRNAs, lncRNAs, circRNAs, and miRNAs related to HPH have been identified from extensive studies, the competitive endogenous RNA (ceRNA) regulatory network in the pulmonary artery that responds to hypoxia remains largely unknown. Results Transcriptomic profiles in the pulmonary arteries of HPH rats were characterized through high-throughput RNA sequencing in this study. Through relatively strict screening, a set of differentially expressed RNAs (DERNAs) including 19 DEmRNAs, 8 DElncRNAs, 19 DEcircRNAs, and 23 DEmiRNAs were identified between HPH and normal rats. The DEmRNAs were further found to be involved in cell adhesion, axon guidance, PPAR signaling pathway, and calcium signaling pathway, suggesting their crucial role in HPH. Moreover, a hypoxia-induced ceRNA regulatory network in the pulmonary arteries of HPH rats was constructed according to the ceRNA hypothesis. More specifically, the ceRNA network was composed of 10 miRNAs as hub nodes, which might be sponged by 6 circRNAs and 7 lncRNAs, and directed the expression of 18 downstream target genes that might play important role in the progression of HPH. The expression patterns of selected DERNAs in the ceRNA network were then validated to be consistent with sequencing results in another three independent batches of HPH and normal control rats. The diagnostic effectiveness of several hub mRNAs in ceRNA network was further evaluated through investigating their expression profiles in patients with pulmonary artery hypertension (PAH) recorded in the Gene Expression Omnibus (GEO) dataset GSE117261. Dysregulated POSTN, LTBP2, SPP1, and LSAMP were observed in both the pulmonary arteries of HPH rats and lung tissues of PAH patients. Conclusions A ceRNA regulatory network in the pulmonary arteries of HPH rats was constructed, 10 hub miRNAs and their corresponding interacting lncRNAs, circRNAs, and mRNAs were identified. The expression patterns of selected DERNAs were further validated to be consistent with the sequencing result. POSTN, LTBP2, SPP1, and LSAMP were suggested to be potential diagnostic biomarkers and therapeutic targets for PAH.

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Screening of Hub Genes Associated with Pulmonary Arterial Hypertension by Integrated Bioinformatic Analysis

Cited by 14 publications

References 67 publications

Loss of Frizzled 9 in Lung Cells Alters Epithelial Phenotype and Promotes Premalignant Lesion Development

Loss of Frizzled 9 in Lung Cells Alters Epithelial Phenotype and Promotes Premalignant Lesion Development

In Silico Analysis of Pulmonary Arterial Hypertension to İdentify Key Biomarkers at Protein and RNA Levels

Decoding ceRNA regulatory network in the pulmonary artery of hypoxia-induced pulmonary hypertension (HPH) rat model

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