Cell-specific expression and function patterns of microRNA-150-5p in liver fibrogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124411 | GEO | 2019/03/01
REPOSITORIES: GEO
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Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress
Project description:With the aim to reveal the function of microRNAs in Hepatic stellate cells (HSCs) in response to portal hypertension, primary rat HSCs were exposed to pressure (10mmHg, 1 h) by using a pressure induced apparatus. Appling next-generation sequencing screened the pressurization induced miRNAs expression profile in HSCs. Among them miR-9a-5p was confirmed to be significantly increased after loading pressure in HSC by RT-PCR. It was found that inhibition of miR-9a-5p could significantly restrain HSCs proliferation and activation under pressure overload. Moreover, the results showed that the induction of miR-9a-5p upon pressure load might by increasing the phosphorylation of Akt but not FAK and Erk1/2. Luciferase reporter assay and western blot suggested that Sirt1 was a potential target gene of miR-9a-5p. Finally, we revealed that miR-9a-5p level was apparently higher in rat liver fibrotic model than in the normal control while Sirt1 level was decreased in fibrotic liver tissue. In conclusion, our results suggest that miR-9a-5p regulate HSCs proliferation through negative regulation of Sirt1 and suggest a potential biomarker for portal hypertension.
2017-08-29 | GSE63783 | GEO
Project description:Background/Aims: Sept4, a subunit of the septin cytoskeleton specifically expressed in quiescent hepatic stellate cells (HSCs), is downregulated through transdifferentiation to fibrogenic and contractile myofibroblastic cells. Since Sept4?/? mice are prone to liver fibrosis, we examined the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. Methods: We compared the transcriptomes of Sept4+/+ and Sept4?/? HSCs by differential DNA microarray analysis and quantitative RT-PCR. Based on reduced dickkopf2 (Dkk2) gene expression in Sept4?/? HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4?/? HSCs. We used a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay to test whether Dkk2 can exert anti-fibrotic effects by interfering with the canonical Wnt pathway. Results: We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride hepatitis model in mice, which decreased with loss of Sept4. Supplementing Dkk2 suppressed the induction of pro-fibrotic genes (?-smooth muscle actin and 2 collagen genes) and induced an anti-fibrotic gene (Smad7) in Sept4?/? HSCs. In human liver specimens with inflammation and fibrosis, Dkk2 immunoreactivity appeared to be positively correlated with the degree of fibrotic changes. Conclusions: Pro-fibrotic transformation of HSCs through the loss of Sept4 is partly due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway. We induced Liver Cirrhosis to SEPT4-KO or wild type mouse by CCl4, and examined mRNA expression profiling in hepatic stellate cell of these mouse.
2012-06-02 | E-GEOD-24588 | biostudies-arrayexpress
Project description:Liver fibrosis is a common pathological process of various chronic liver diseases that can develop into liver cancer. MicroRNAs (miRNAs) are a king of non-coding RNA which are closely related to liver diseases. Thus, this research hope to explore the effect of miR-484 on liver fibrosis and reveal its mechanism. The miRNAs profiles were screened by microRNA sequencing and the location of miR-484 was identified by fluorescence in situ hybridization (FISH) in human liver fibrotic tissues. MiR-484 expression was detected by qRT-PCR in rat primary hepatic stellate cells (HSCs). Bioinformatics analysis and dual-luciferase reporter assay were performed to determine the target gene of miR-484. Liver fibrosis specific signatures were analyzed by qRT-PCR and western blot after miR-484 mimic/inhibitor transfection. The cell apoptosis was detected by Annexin V-FITC/PI double staining. The effect of miR-484 silencing on fibrosis in vivo was investigated in thioacetamide (TAA) induced mice model using the adeno-associated virus carrying miR-484 inhibitor. Enrichment of miR-484 was observed in human liver fibrosis tissues and activated rat primary HSCs. FISH showed that miR-484 was prominently located at fibrotic region and the cytoplasm of HSCs in human liver tissues. Dual-luciferase reporter assay verified that the homeodomain-interacting protein kinases 1 (HIPK1) was the direct target of miR-484. After transfecting miR-484 inhibitor into HSC-T6, HIPK1 were significantly up-regulated, and α-SMA, col1a1, Wnt-3a, Wnt-5a, β-catenin and p-β-catenin were down-regulated, suggesting the restrain effect of miR-484 knockdown on HSCs activation. Conversely, the results were opposite with miR-484 mimic transfection. In addition, the apoptosis of HSC-T6 altered significantly after miR-484 modulation. Moreover, adeno-associated virus carrying miR-484 inhibitor alleviated mice liver fibrosis induced by TAA. In conclusion, miR-484 knockdown ameliorates liver fibrosis by promoting the apoptosis and suppressing HSCs activation via blocking Wnt/β-catenin signaling pathway. MiR-484 and its downstream gene HIPK1 might be selected as novel therapeutic targets of liver fibrosis.
2021-12-09 | GSE190366 | GEO
Project description:Liver fibrosis is a reversible wound-healing response to liver injury and hepatic stellate cells (HSCs) are central cellular players that mediate hepatic fibrogenesis. However, the molecular mechanisms that govern this process remain unclear. Here, we reveal a novel cistromic circuit in HSCs comprising the vitamin D receptor (VDR) and SMAD transcription factors that restrains the intensity of hepatic fibrogenesis. Ligand-activated VDR suppresses TGFβ1-induced pro-fibrotic gene expression in HSCs. Administration of a vitamin D analogue, calcipotriol, diminishes the fibrotic response in a mouse model of liver fibrosis, while VDR knockout mice spontaneous develop extensive hepatic fibrosis by age 6 months. Using ChIP-Seq, we find that the anti-fibrotic properties of VDR are due to crosstalk with SMAD, mediated by their co-occupancy of DNA-binding sites on pro-fibrotic genes. Specifically, SMAD binding potentiates local chromatin accessibility to enhance VDR recruitment at the same cis-regulatory elements, which reciprocally antagonizes the interaction between SMAD3 and chromatin and limits the assembly of transcriptional activation complexes at fibrotic genes, a process that is enhanced by the presence of VDR agonists. These results not only establish this coordinated VDR/SMAD cistromic circuit as a master regulator of hepatic fibrogenesis, but also support VDR as a potential drug target to ameliorate liver fibrosis. Identification of VDR, SMAD3 and H3 binding sites in human stellate LX2 cells that were pre-treated with calcipotriol (100nM) for 16 hrs (where calcipotriol treatment is indicated) followed by incubation of calcipotriol (100nM) or TGFβ1 (1ng/ml) for another 4 hours (where indicated).
2013-04-29 | E-GEOD-38103 | biostudies-arrayexpress
Project description:Purpose: We recently identified 39 human microRNAs, which effectively suppress hepatitis B virus (HBV) replication in hepatocytes. Because chronic HBV infection often results in active, hepatitis-related liver fibrosis, we assessed whether any of these microRNAs have anti-fibrotic potential and predicted that miR-6133-5p may target several fibrosis-related genes. Methods: The hepatic stellate cell line LX-2 was transfected with miR-6133-5p mimic and subsequently treated with TGF-β. mRNA and protein products of COL1A1, encoding collagen, and ACTA2, an activation marker of hepatic stellate cells, were quantified. Results: Expression of COL1A1 and ACTA2 was markedly reduced in LX-2 cells treated with miR-6133-5p. Interestingly, phosphorylation of JNK also was significantly decreased by miR-6133-5p treatment. The expression of several predicted target genes of miR-6133-5p, including TGFBR2 and FGFR1, was also reduced in miR-6133-5p-treated cells. The knockdown of TGFBR2 by the corresponding small interfering RNA greatly suppressed the expression of COL1A1 and ACTA2. Treatment with the JNK inhibitor, SP600125, also suppressed COL1A1 and ACTA2 expression, indicating that TGFBR2 and JNK would mediate the anti-fibrotic effect of miR-6133-5p. Downregulation of FGFR1 may result in a decrease of phosphorylated AKT, ERK, and JNK. Conclusions: miR-6133-5p has a strong anti-fibrotic effect, mediated by inactivation of TGFBR2, AKT and JNK.
2020-09-25 | GSE158478 | GEO
Project description:Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis.
2020-12-22 | GSE153581 | GEO
Project description:Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis.
2020-12-22 | GSE153580 | GEO
Project description:Liver fibrosis, results from the imbalance between extracellular matrix (ECM) production and degradation, is a common pathological consequence of various chronic liver diseases. Although a large number of miRNAs have been reported in liver fibrosis progression, miRNA-mRNA interactions involved in its reversal process remain to be fully elucidated. In the current study, we performed an integrated analysis of miRNA and mRNA expression profiles in a hepatic fibrosis recovery mouse model induced by thioacetamide. A total of 102 miRNA and 2,845 mRNAs showed significant differential expression in recovery mice compared to fibrotic mice. Moreover, 3,769 putative negatively correlated miRNA-mRNA pairs were revealed to be potentially implicated in the biological function regulation of small molecule metabolism and ECM organization. By integrating miRNA-mRNA regulatory networks, mmu-miR-1843a-5p, mmu-miR-193a-5p, mmu-miR-194-2-3p and mmu-miR-30c-2-3p were identified as lysyl oxidase-specific miRNAs that were associated with the pathogenesis of fibrosis recovery. Our results provide potential novel biomarkers and candidate targets for the treatment of liver fibrosis.
2022-04-26 | GSE173961 | GEO
Project description:Liver fibrosis, results from the imbalance between extracellular matrix (ECM) production and degradation, is a common pathological consequence of various chronic liver diseases. Although a large number of miRNAs have been reported in liver fibrosis progression, miRNA-mRNA interactions involved in its reversal process remain to be fully elucidated. In the current study, we performed an integrated analysis of miRNA and mRNA expression profiles in a hepatic fibrosis recovery mouse model induced by thioacetamide. A total of 102 miRNA and 2,845 mRNAs showed significant differential expression in recovery mice compared to fibrotic mice. Moreover, 3,769 putative negatively correlated miRNA-mRNA pairs were revealed to be potentially implicated in the biological function regulation of small molecule metabolism and ECM organization. By integrating miRNA-mRNA regulatory networks, mmu-miR-1843a-5p, mmu-miR-193a-5p, mmu-miR-194-2-3p and mmu-miR-30c-2-3p were identified as lysyl oxidase-specific miRNAs that were associated with the pathogenesis of fibrosis recovery. Our results provide potential novel biomarkers and candidate targets for the treatment of liver fibrosis.
2022-04-26 | GSE173456 | GEO