<scp>miR</scp>‐30c and <scp>miR</scp>‐193 are a part of the <scp>TGF</scp>‐β‐dependent regulatory network controlling extracellular matrix genes in liver fibrosis

Roy, Sanchari; Benz, Fabian; Cardenas, David Vargas; Vucur, Mihael; Gautheron, Jérémie; Schneider, Anne T.; Hellerbrand, Claus; Pottier, Nicolas; Alder, Jan; Tacke, Frank; Trautwein, Christian; Roderburg, Christoph; Luedde, Tom

doi:10.1111/1751-2980.12266

Cited by 60 publications

(52 citation statements)

References 37 publications

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“…When the liver is subjected to chronic injury, hepatic stellate cells (HSCs) are activated and proliferate, causing ECM deposition, and hepatocytes are replaced with abundant ECM (Duval et al, 2014) which leads to scar formation and fibrosis (Roy et al, 2015), which were proved in Sirius red staining. ECM-involved signaling was also reported to be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis (Karsdal et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

et al. 2016

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-The classic toxicity of carbon tetrachloride (CCl 4 ) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl 4 -induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl 4 in liver fibrosis. Wistar rats were treated with CCl 4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl 4 -treated group were significantly higher than that of CCl 4 -untreated group. CCl 4 -treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl 4 treatment. Therefore, the toxicological mechanisms of CCl 4 -induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl 4 detoxication in the liver.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

et al. 2016

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“…This cohort has been previously described [24]. miR-192-5p serum concentrations were measured in serum of 28 acute liver failure (ALF) patients.…”

Section: Patient Cohorts Analysedmentioning

confidence: 99%

Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury

et al. 2016

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miR-192-5p has gained increasing relevance in various diseases, however, its function in acute liver injury is currently unknown. We analysed miR-192-5p serum levels and hepatic miR-192-5p expression in mice after hepatic ischaemia and reperfusion (I/R) as well as in toxic liver injury. On a functional level, miRNA levels were analysed in the different hepatic cell-compartments and in the context of tumour necrosis factor (TNF)-dependent liver cell death. We detected increased serum levels of miR-192-5p after hepatic I/R- and carbon tetrachloride (CCl4)-induced liver injury. miR-192-5p levels correlated with the degree of liver damage and the presence of hepatic cell death detected by TUNEL stainings (terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labelling stainings). Moreover, expression of miR-192-5p was increased in a hypoxia/reoxygenation (H/R) model of in vitro hepatocyte injury, supporting that the passive release of miR-192-5p represents a surrogate for hepatocyte death in liver injury. In critically ill patients, miR-192-5p levels were elevated selectively in patients with liver injury and closely correlated with the presence of hepatic injury. In contrast with up-regulated miR-192-5p in the serum, we detected a down-regulation of miR-192-5p in both injured mouse and human livers. Deregulation of miR-192-5p in livers was dependent on stimulation with TNF. Functional experiments confirmed a protective effect of down-regulation of miR-192-5p in hepatocytes, suggesting a role of miR-192-5p in limiting liver injury. Finally, we identified Zeb2, an important regulator of cell death, as a potential target gene mediating the function of miR-192-5p Our data suggest that miR-192-5p is involved in the regulation of liver cell death during acute liver injury and might represent a potent marker of hepatic injury.

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“…Upregulation was also identified for miR-199a-5p/199a-3p and miR-221/222 in hepatitis C induced liver fibrosis in a fibrosis progression-dependent manner. [31] Members of the miR-17-92 cluster (19a, 19b, 92a) [32], miR-29, miR-133, miR-193 and miR-30c [33,34] were observed to be specifically downregulated in human liver fibrosis and HSC, while they showed a reciprocal expression pattern after recovery from liver fibrosis. Reduced expression of miR-144 was correlated with elevated HSC-specific expression of transforming growth factor-β1 (TGF-β1) and expression of α-SMA in fibrotic liver tissues.…”

Section: Clinical Relevance Of Mir In Cafmentioning

confidence: 99%

“…[57] The miR-193b/-365a cluster is also involved in cytokine related cell-cell communication. TGF-β-dependent downregulation has been identified involving Snail-1, an important regulator of extracellular matrix in HSCs [33]. Suppressed NF-κB dependent p65 activation inhibits miR-365 expression with resulting increased IL-6 secretion within the cancer environment.…”

Section: Soluble Factorsmentioning

confidence: 99%

MicroRNAs in the Communication between Cancer Associated Fibroblasts (CAF) and Cancer Cells

M¹,

Aj²,

Haier³

2017

Preprint

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Tumor microenvironment including cancer-associated fibroblasts (CAF) has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell -tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF into their pathological counterparts. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

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miR‐30c and miR‐193 are a part of the TGF‐β‐dependent regulatory network controlling extracellular matrix genes in liver fibrosis

Abstract: These results suggest that miR-30 and miR-193 are members of a network of miRNAs modifying the TGF-β-dependent regulation of extracellular matrix-related genes in HSCs in the manifestation and resolution of liver fibrosis.

Cited by 60 publications

References 37 publications

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

Mechanisms of CCl<sub>4</sub>-induced liver fibrosis with combined transcriptomic and proteomic analysis

Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury

MicroRNAs in the Communication between Cancer Associated Fibroblasts (CAF) and Cancer Cells

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