MicroRNA profiling identifies miR-2355-5p as a key modulator in Renal Cell Carcinoma tumor growth
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ABSTRACT:
PROVIDER: PRJNA1035146 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26661289_1.fastq.gz | Fastqsanger.gz | |||
| SRR26661289_2.fastq.gz | Fastqsanger.gz | |||
| SRR26661290_1.fastq.gz | Fastqsanger.gz | |||
| SRR26661290_2.fastq.gz | Fastqsanger.gz | |||
| SRR26661291_1.fastq.gz | Fastqsanger.gz |
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Project description:Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal event in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. Accumulation of the Hypoxia Induced Factors (HIFα) acquired from VHL loss can promote ccRCC tumorigenesis through regulating microRNAs (miRNA) expression. Here, we performed a miRNA profiling and used high throughput analysis to identify a panel of VHL dependent miRNAs in ccRCC. Validation of these miRNAs uncovered overexpression of miR-2355-5p in ccRCC cell models, and primary tumors. Moreover, we showed a significant increase of circulating miR-2355-5p in plasma from patients with ccRCC. Mechanistically, miR-2355-5p overexpression was confirmed to be HIF-2α-dependent. Indeed, targeting miR-2355-5p with the CRISPR/cas9 system did not only negatively disturbed ccRCC cell’s ability to stimulate angiogenesis, but also decreased cell proliferation and drastically reduced tumor growth in mice xenograft models. Finally, miR-2355-5p pulldown assay identified five tumor suppressor genes, ACO1, BTG2, CMTM4, SLIT2, and WDFY2, as potential targets. All five genes were significantly downregulated in ccRCC tumors and mice xenograft tumors. Results from this research demonstrate the oncogenic ability of miR-2355-5p and shed light on the possible route in which the miRNA controls angiogenesis and tumor growth in VHL-deficient ccRCC
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Project description:Adult renal stem/progenitor cells (ARPCs), first identified in the BowmanM-bM-^@M-^Ys capsule, were recently identified also in the tubular compartment and it was demonstrated that renal progenitors from both locations were positive for PAX-2, CD133 and CD24 and exhibited multipotent differentiation ability. Recent studies indicated that microRNAs (miRNAs), a class of noncoding small RNAs that participate in the regulation of gene expression, may play a key role in stem cell self-renewal and differentiation. Distinct sets of miRNAs are specifically expressed in pluripotent stem cells but not in adult tissues, suggesting a role for miRNAs in stem cell self-renewal. We compared miRNA expression profiles of renal progenitors with that of renal proximal tubular cells (RPTECs) and of mesenchymal stem cells (MSC) and found distinct sets of miRNAs that were specifically expressed both in tubular and glomerular ARPCs. In particular, the miR-1915 and miR-1225-5p regulated the expression of important markers of renal progenitors, such as CD133 and PAX-2, and important genes involved in the repair mechanisms of ARPCs, such as TLR2. We demonstrated that the expression of both the renal stem cell markers CD133 and PAX-2 depends, at least in part, on lower miR-1915 levels and showed that the increase of miR-1915 levels improved capacity of ARPCs to differentiate into adipocyte-like and epithelial-like cells. Finally, we found that the low levels of miR-1225-5p were responsible for high TLR2 expression in ARPCs. Therefore, together, the miR-1915 and the miR-1225-5p seems to regulate important trait of ARPCs: the stemness and the repair capacity. Sixteen samples consisting of 5 glomerular and tubular ARPCs each, 3 MSCs, and 3 RPTECS.
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Project description:Aldosterone controls sodium homeostasis by binding to the Mineralocorticoid Receptor (MR). We previously identified a specific temporal window during renal development when MR expression is low, explaining the physiological sodium losses observed in newborns at birth. However, underlying molecular mechanisms controlling MR expression remain unknown. Recently, we demonstrated in adult renal KC3AC1 cell line that MR expression is controlled by microRNAs (miR-30c-2-3p and miR-324-5p) in response to tonicity. Herein, we highlight the involvement of two microRNAs (miR-409-3p and miR-431-5p) in the regulation of MR expression during the neonatal period. RT-qPCR validated candidates microRNAs identified by high throughput screening approach and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Underexpression strategies using Inhibitors revealed the impact on MR expression and signaling in primary culture renal cells. miR-409-3p and miR-431-5p are increased at D0 in mirror to MR expression. These miRNAs directly affect Nr3c2 (MR) transcript stability and enhances MR expression and signaling at D0. Whereas, overexpression strategies using Mimics, destabilize MR expression and mineralocorticoid signaling in primary culture renal cells at D8. We also confirm that their expression is increased in urine from neonates at birth, an expression that gradually decreased after birth (PREMALDO cohort). Finally, we performed an RNA sequencing to evaluate an integrative network of miRNAs and mRNA differentially expressed between D0 and D8. Differentially expressed genes (DEG) were crossed with the two candidate miRNAs, and 83 differentially expressed target genes (DETG) were obtained. Functional annotation suggested that kidney development and sodium transport/homeostasis pathways were significantly enriched. Our findings provide new predictive and non-invasive biomarkers of renal maturity and mineralocorticoid signaling expression and efficacy in human premature infants.
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Project description:Aldosterone controls sodium homeostasis by binding to the Mineralocorticoid Receptor (MR). We previously identified a specific temporal window during renal development when MR expression is low, explaining the physiological sodium losses observed in newborns at birth. However, underlying molecular mechanisms controlling MR expression remain unknown. Recently, we demonstrated in adult renal KC3AC1 cell line that MR expression is controlled by microRNAs (miR-30c-2-3p and miR-324-5p) in response to tonicity. Herein, we highlight the involvement of two microRNAs (miR-409-3p and miR-431-5p) in the regulation of MR expression during the neonatal period. RT-qPCR validated candidates microRNAs identified by high throughput screening approach and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Underexpression strategies using Inhibitors revealed the impact on MR expression and signaling in primary culture renal cells. miR-409-3p and miR-431-5p are increased at D0 in mirror to MR expression. These miRNAs directly affect Nr3c2 (MR) transcript stability and enhances MR expression and signaling at D0. Whereas, overexpression strategies using Mimics, destabilize MR expression and mineralocorticoid signaling in primary culture renal cells at D8. We also confirm that their expression is increased in urine from neonates at birth, an expression that gradually decreased after birth (PREMALDO cohort). Finally, we performed an RNA sequencing to evaluate an integrative network of miRNAs and mRNA differentially expressed between D0 and D8. Differentially expressed genes (DEG) were crossed with the two candidate miRNAs, and 83 differentially expressed target genes (DETG) were obtained. Functional annotation suggested that kidney development and sodium transport/homeostasis pathways were significantly enriched. Our findings provide new predictive and non-invasive biomarkers of renal maturity and mineralocorticoid signaling expression and efficacy in human premature infants.
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Project description:Adult renal stem/progenitor cells (ARPCs), first identified in the Bowman’s capsule, were recently identified also in the tubular compartment and it was demonstrated that renal progenitors from both locations were positive for PAX-2, CD133 and CD24 and exhibited multipotent differentiation ability. Recent studies indicated that microRNAs (miRNAs), a class of noncoding small RNAs that participate in the regulation of gene expression, may play a key role in stem cell self-renewal and differentiation. Distinct sets of miRNAs are specifically expressed in pluripotent stem cells but not in adult tissues, suggesting a role for miRNAs in stem cell self-renewal. We compared miRNA expression profiles of renal progenitors with that of renal proximal tubular cells (RPTECs) and of mesenchymal stem cells (MSC) and found distinct sets of miRNAs that were specifically expressed both in tubular and glomerular ARPCs. In particular, the miR-1915 and miR-1225-5p regulated the expression of important markers of renal progenitors, such as CD133 and PAX-2, and important genes involved in the repair mechanisms of ARPCs, such as TLR2. We demonstrated that the expression of both the renal stem cell markers CD133 and PAX-2 depends, at least in part, on lower miR-1915 levels and showed that the increase of miR-1915 levels improved capacity of ARPCs to differentiate into adipocyte-like and epithelial-like cells. Finally, we found that the low levels of miR-1225-5p were responsible for high TLR2 expression in ARPCs. Therefore, together, the miR-1915 and the miR-1225-5p seems to regulate important trait of ARPCs: the stemness and the repair capacity.
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2020-11-04 | PXD022358 |
Project description:Renal interstitial fibrosis (RIF) is a common pathological feature and final manifestation of chronic progressive kidney disease. Although exosome-mediated intercellular communication is known to play a crucial role in RIF, the mechanism by which injured tubular epithelial cells (TECs) contribute to fibrogenesis remains incompletely understood. In this study, we investigated the role of exosomal miR-122-5p derived from TECs in modulating fibroblast activation and renal fibrosis. Exosomes were isolated from kidneys of unilateral ureteral obstruction (UUO) mice and from TGF-β1-stimulated HK-2 cells. These exosomes were either co-cultured with fibroblasts (NRK-49F cells) or injected into UUO mice via the tail vein. High-throughput miRNA profiling was used to identify differentially expressed miRNAs in exosomes derived from HK-2 cells, and miR-122-5p was selected for further investigation based on expression level and bioinformatic prediction. Functional analyses were performed using miRNA mimics, inhibitors, and target validation assays. The results showed that exosomal miR-122-5p was significantly downregulated in both fibrotic kidneys and TGF-β1-induced HK-2 cells. In vivo and in vitro, restoration of miR-122-5p levels markedly attenuated renal fibrosis, as evidenced by the reduction of fibrotic markers including α-smooth muscle actin, fibronectin, and collagen I. Mechanistically, miR-122-5p was found to directly target hypoxia-inducible factor 1-alpha (HIF-1α), thereby inhibiting activation of the TGF-β1/Smad signaling pathway. These findings suggest that decreased expression of miR-122-5p in TEC-derived exosomes promotes renal fibrosis through the HIF-1α/TGF-β1/Smad axis, while reintroduction of miR-122-5p can effectively reverse these effects. Taken together, our study provides new insights into the intercellular communication between TECs and fibroblasts via exosomal miRNAs, and identifies miR-122-5p as a potential therapeutic target for the treatment of renal interstitial fibrosis.
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