Abstract:Previous studies have demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) induces blood-tumor barrier (BTB) hyperpermeability via both paracellular and transcellular pathways. In a recent study, we revealed that cAMP/PKA-dependent and cAMP/PKA-independent signaling pathways are both involved in EMAP-II-induced BTB hyperpermeability. The present study further investigated the exact mechanisms through which the cAMP/PKA-independent signaling pathway affects EMAP-II-induced BTB hyp… Show more
“…KEGG functional enrichment analysis showed that up-regulated DhMGs in the lung cancer group are mainly enriched in nicotine addition, calcium signaling pathway, and circadian entrainment pathways, which are closely associated with cancer development [32] , [33] ( Figure 4 E). Genes with decreased 5hmC signal were enriched in several cancer- and metastasis-related pathways including platelet activation pathway, cGMP-PKG signaling pathway, Rap signaling pathway, and PI3K-Akt signaling pathway [34] , [35] ( Figure 4 F). Figure 4 Identified DhMGs as candidate biomarkers to distinguish blood samples from healthy controls and NSCLC patients A. Genome browser view of the cell-free 5hmC distribution in LDB2 (one example of differentially-methylated genes) loci in control and tumor samples.…”
Non-small-cell lung cancer (NSCLC), the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminating tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identified six potential biomarkers from 66 patients and 67 healthy controls (mean decrease accuracy >3.2, P < 3.68E−19) using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient’s cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC.
“…KEGG functional enrichment analysis showed that up-regulated DhMGs in the lung cancer group are mainly enriched in nicotine addition, calcium signaling pathway, and circadian entrainment pathways, which are closely associated with cancer development [32] , [33] ( Figure 4 E). Genes with decreased 5hmC signal were enriched in several cancer- and metastasis-related pathways including platelet activation pathway, cGMP-PKG signaling pathway, Rap signaling pathway, and PI3K-Akt signaling pathway [34] , [35] ( Figure 4 F). Figure 4 Identified DhMGs as candidate biomarkers to distinguish blood samples from healthy controls and NSCLC patients A. Genome browser view of the cell-free 5hmC distribution in LDB2 (one example of differentially-methylated genes) loci in control and tumor samples.…”
Non-small-cell lung cancer (NSCLC), the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminating tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identified six potential biomarkers from 66 patients and 67 healthy controls (mean decrease accuracy >3.2, P < 3.68E−19) using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient’s cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC.
“…Furthermore, Rap1 is considered as a protein that can revert Ras transformation, and it is a key mediator in the control of integrin activation ( 36 ). A recent study revealed that the cAMP/Epac/Rap1 signaling cascade had a crucial role in blood-tumour barrier hyperpermeability ( 37 ). Cancer cell-induced platelet activation is identified as a critical event responsible for prometastatic activity of platelets, and blocking platelet aggregation can inhibit the progression of skeletal metastases, yet the mechanism underlying this effect is still unknown ( 38 ).…”
Osteosarcoma is a common and highly malignant tumour in children and teenagers that is characterized by drug resistance and high metastatic potential. Patients often develop pulmonary metastasis and have a low survival rate. However, the mechanistic basis for pulmonary metastasis remains unclear. To identify key gene and pathways associated with pulmonary metastasis of osteosarcoma, the authors downloaded the gene expression dataset GSE85537 and obtained the differentially expressed genes (DEGs) by analyzing high-throughput gene expression in primary tumours and lung metastases. Subsequently, the authors performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses and a protein-protein interaction (PPI) network was constructed and analyzed by Cytoscape software. In total, 2,493 genes were identified as DEGs. Of these, 485 genes (19.45%) were upregulated, and the remaining 2,008 genes (80.55%) were downregulated. The authors identified the predominant GO categories and KEGG pathways that were significantly over-represented in the metastatic OS samples compared with the non-metastatic OS samples. A PPI network was constructed, and the results indicated that ALB, EGFR, INS, IL6, CDH1, FYN, ERBB2, IL8, CXCL12 and RAC2 were the top 10 core genes. The enrichment analyses of the genes involved in the top three significant modules demonstrated that the DEGs were principally related to neuroactive ligand-receptor interaction, the Rap1 signaling pathway, and protein digestion and absorption. Together, these data elucidated the molecular mechanisms of OS patients with pulmonary metastasis and provide potential therapeutic targets. However, further experimental studies are needed to confirm these results.
“…To gain insight into the pathways mediated by EPAC, the protein levels of both Rap1-GDP and total Rap1 were determined. EPAC have been viewed as a family of D r a f t cAMP-responsive GEFs for Rap1 (Li et al 2015). Data from our recent study showed that Me-cAMP upregulated it while total Rap1 proteins remained unchanged.…”
Section: Yokoyama Et Al Reported That Tgfβ1 Decreases Transcriptionamentioning
Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 μmol/L acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA). Our data showed that both cAMP/PKA and cAMP/EPAC signaling pathways were involved in acetaldehyde-induced HSCs. Acetaldehyde could reduce the expression of EPAC1 while enhancing the expression of EPAC2. The cAMP analog Me-cAMP, which stimulates the EPAC/Rap1 pathway, could significantly decrease the proliferation and collagen synthesis of acetaldehyde-induced HSCs. Furthermore, depletion of EPAC2, but not EPAC1, prevented the activation of HSC measured as the production of α-SMA and collagen type I and III, indicating that EPAC1 appears to have protective effects on acetaldehyde-induced HSCs. Curiously, activation of PKA or EPAC perhaps has opposite effects on the synthesis of collagen and α-SMA: EPAC activation by Me-cAMP increased the levels of GTP-bound (activated) Rap1 while PKA activation by Phe-cAMP had no significant effects on such binding. These results suggested that EPAC activation could inhibit the activation and proliferation of acetaldehyde-induced HSCs via Rap1.
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