Deletion of the miR-25/93/106b cluster induces glomerular deposition of immune complexes and renal fibrosis in mice.
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ABSTRACT:
SUBMITTER: Ma H
PROVIDER: S-EPMC8358857 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increased reactive oxygen species levels in the mitochondrial matrix can induce Parkin-dependent mitophagy, which selectively degrades dysfunctional mitochondria via the autolysosome pathway. Phosphorylated mitofusin-2 (MFN2), a receptor of parkin RBR E3 ubiquitin-protein ligase (Parkin), interacts with Parkin to promote the ubiquitination of mitochondrial proteins; meanwhile, the mitophagy receptors Optineurin (OPTN) and nuclear dot protein 52 (NDP52) are recruited to damaged mitochondria to promote mitophagy. However, previous studies have not investigated changes in the levels of OPTN, MFN2, and NDP52 during Parkin-mediated mitophagy. Here, we show that mild and sustained hydrogen peroxide (H2O2) stimulation induces Parkin-dependent mitophagy accompanied by downregulation of the mitophagy-associated proteins OPTN, NDP52, and MFN2. We further demonstrate that H2O2 promotes the expression of the miR-106b-93-25 cluster and that miR-106b and miR-93 synergistically inhibit the translation of OPTN, NDP52, and MFN2 by targeting their 3' untranslated regions. We further reveal that compromised phosphorylation of MYC proto-oncogene protein (c-Myc) at threonine 58 (T58) (producing an unstable form of c-Myc) caused by reduced nuclear glycogen synthase kinase-3 beta (GSK3β) levels contributes to the promotion of miR-106b-93-25 cluster expression upon H2O2 induction. Furthermore, miR-106b-mediated and miR-93-mediated inhibition of mitophagy-associated proteins (OPTN, MFN2, and NDP52) restrains cell death by controlling excessive mitophagy. Our data suggest that microRNAs (miRNAs) targeting mitophagy-associated proteins maintain cell survival, which is a novel mechanism of mitophagy control. Thus, our findings provide mechanistic insight into how miRNA-mediated regulation alters the biological process of mitophagy.
| S-EPMC7904769 | biostudies-literature
Project description:Lung cancer is the first cause of cancer death worldwide and the Hippo pathway transcriptional coactivators YAP/TAZ have a pro-oncogenic role in this context. In order to understand the mechanisms through which YAP/TAZ elicit their oncogenic role in different systems, many studies are focused on YAP/TAZ target genes involved in the regulation of cell proliferation/survival and migration. However, there is scarce evidence on the role of YAP/TAZ in microRNA regulation while there is increasing evidence supporting the role of microRNAs in the main oncogenic processes. Here, we showed that YAP/TAZ were able to regulate several microRNAs in non-small cell lung cancer (NSCLC) cell lines. In detail, we focused on a cluster of three oncogenic microRNAs (miR-25, 93 and 106b) hosted in the MCM7 gene that were overexpressed in lung tumors compared to normal tissues. In addition, similar behavior was observed in breast cancer and head and neck tumor casuistries, where they showed a prognostic role. In NSCLC cells, YAP/TAZ induced the transcription of the MCM7 gene and its hosted miRs, thereby promoting cell proliferation through the post-transcriptional inhibition of the p21 cell cycle regulator. Accordingly, p21 was maintained at low levels in lung tumors compared to normal tissues. Conversely, its expression was restored in NSCLC cells upon YAP/TAZ interference or upon treatment with the statin cerivastatin. In summary, we provide evidence for a novel mechanism of modulation supporting the protumorigenic functions of the YAP/TAZ factors through the modulation of a bioncogenic locus consisting of one gene and three hosted microRNAs.
| S-EPMC6276925 | biostudies-literature
Project description:The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.
| S-EPMC5400610 | biostudies-literature
Project description:Histone deacetylase (HDAC) inhibitors are emerging as a novel class of anti-tumor agents and have manifested the ability to decrease proliferation and increase apoptosis in different cancer cells. A significant number of genes have been identified as potential effectors responsible for the anti-tumor function of HDAC inhibitor. However, the molecular mechanisms of these HDAC inhibitors in this process remain largely undefined. In the current study, we searched for microRNAs (miRs) that were affected by HDAC inhibitor trichostatin (TSA) and investigated their effects in endometrial cancer (EMC) cells. Our data showed that TSA significantly inhibited the growth of EMC cells and induced their apoptosis. Among the miRNAs that altered in the presence of TSA, the miR-106b-93-25 cluster, together with its host gene MCM7, were obviously down-regulated in EMC cells. p21 and BIM, which were identified as target genes of miR-106b-93-25 cluster, increased in TSA treated tumor cells and were responsible for cell cycle arrest and apoptosis. We further identified MYC as a regulator of miR-106b-93-25 cluster and demonstrated its down-regulation in the presence of TSA resulted in the reduction of miR-106b-93-25 cluster and up-regulation of p21 and BIM. More important, we found miR-106b-93-25 cluster was up-regulated in clinical EMC samples in association with the overexpression of MCM7 and MYC and the down-regulation of p21 and BIM. Thus our studies strongly indicated TSA inhibited EMC cell growth and induced cell apoptosis and cell cycle arrest at least partially through the down-regulation of the miR-106b-93-25 cluster and up-regulation of it's target genes p21 and BIM via MYC.
| S-EPMC3446970 | biostudies-literature
Project description:Background:Osteosarcoma (OS) is the most common primary malignant bone tumour in dogs and human beings, characterised by similar genetic and clinical features. With the aim to define similarities and differences in the biological aspects involved in OS progression, a comparative study was performed to create a model to improve patient outcome. Methods:First, the expression of microRNAs (miRNAs) belonging to the cluster miR-106b-25 (miR-106b, miR-25 and miR-93-5p) in human and canine OS tissue was compared. Results:miR-25 and miR-106b presented a variable expression not significantly different from the corresponding normal bone, while miR-93-5p expression was increased in all OS specimens, with higher levels in the canine subset compared with human. Accordingly, its target p21 presented a weaker and less homogeneous immunostaining distribution in the canine group. Given the high expression of miR-93-5p in all OS specimens, the functional response of human 143B and canine DAN OS cells to miRNA inhibition was evaluated. Although p21 expression increased after miR-93-5p inhibition both at mRNA and protein level, a more significant cell response in terms of proliferation and apoptosis was seen in canine OS cells. Conclusions:In conclusion, canine OS tissue and cell line presented higher expression levels of miR-93-5p than human OS. In addition, the introduction of miR-93-5p inhibitor caused a cell response in 143B and DAN that differed for the more intense functional impact in the canine OS cell line.
| S-EPMC7061892 | biostudies-literature
Project description:The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements.
| S-EPMC5217027 | biostudies-literature
Project description:Activation of the unfolded protein response sensor PKR-like endoplasmic reticulum kinase (Perk) attenuates endoplasmic reticulum (ER) stress levels. Conversantly, if the damage is too severe and ER function cannot be restored, this signaling branch triggers apoptosis. Bcl-2 homology 3-only family member Bim is essential for ER stress-induced apoptosis. However, the regulatory mechanisms controlling Bim activation under ER stress conditions are not well understood. Here, we show that downregulation of the miR-106b-25 cluster contributes to ER stress-induced apoptosis and the upregulation of Bim. Hypericin-mediated photo-oxidative ER damage induced Perk-dependent cell death and led to a significant decrease in the levels of miRNAs belonging to miR-106b-25 cluster in wild-type (WT) but not in Perk?/? MEFs. Further, we show that expression of miR-106b-25 and Mcm-7 (host gene of miR-106b-25) is co-regulated through the transcription factors Atf4 (activating transcription factor 4) and Nrf2 (nuclear factor-erythroid-2-related factor 2). ER stress increased the activity of WT Bim 3'UTR (untranslated region) construct but not the miR-106b-25 recognition site-mutated Bim 3'UTR construct. Overexpression of miR-106b-25 cluster inhibits ER stress-induced cell death in WT but did not confer any further protection in Bim-knockdown cells. Further, we show downregulation in the levels of miR-106b-25 cluster in the symptomatic SOD1(G86R) transgenic mice. Our results suggest a molecular mechanism whereby repression of miR-106b-25 cluster has an important role in ER stress-mediated increase in Bim and apoptosis.
| S-EPMC3388242 | biostudies-literature
Project description:BackgroundmiRNA 106b~25 cluster were demonstrated to be an oncogene. In previous study, we had analyzed the diagnostic significance of miRNA 106b~25 based on its carcinogenesis effect. The significance of miRNA 106b~25 for prognosis of gastric cancer were not researched.MethodsWe applied multivariate analysis of PCA, PLS-DA and Cox Regression for clinicopathological features and survival time to explore the significance of miRNA 106b~25 expression in plasma and cancer tissues for gastric cancer.ResultsThe expression of miRNA 106b, miRNA 93 and miRNA 25 in plasma were positively correlated with their expression in tumor tissues. Via PCA analysis, it was found that miRNA 106b~25 expression in plasma and tumor, T, N and TNM stage were correlated with each other. Via PLS-DA analysis, we identified that T, N and TNM stage were important factors for miRNA 106b~25 expression both in plasma and tumor (all VIP value > 1.2). According to loading weights of variables for the first and second components, it was found that the importance of the miRNA 106b~25s expression carried with the progressed stage of gastric cancer. In the survival analysis, COX regression showed that T stage, plasma miRNA 106b and tumor miRNA 93 were significant risk factors for overall survival [HR: 0.400 (0.205-0.780); P = 0.007; HR: 0.371 (0.142-0.969), P = 0.043; 0.295 (0.134-0.650), P = 0.002].ConclusionPlasma and tumor miRNA 106b~25 expression correlated with T, N and TNM stage. Increased miRNA 106b~25 expression was important characters carried with gastric cancer progression. T stage, plasma miRNA106b and tumor miRNA 93 significant risk factors for overall survival.
| S-EPMC6664745 | biostudies-literature
Project description:We and others previously reported that the miR-106b-25 microRNA cluster is a candidate oncogene in human prostate cancer. Here, we made the novel observation that miR-106b-25 expression is further up-regulated in distant metastasis. Moreover, increased tumor miR-106b expression was associated with early disease recurrence. To identify yet unknown oncogenic functions of the prognostic miR-106b, we overexpressed it in LNCaP human prostate cancer cells to examine miR-106b-induced global expression changes among protein-coding genes. The approach revealed that caspase-7 is a candidate direct target of miR-106b, which was confirmed by Western blot analysis and a 3’UTR reporter assay. Other analyses showed that caspase-7 is down-regulated in primary human prostate tumors and metastatic lesions across multiple datasets and is by itself associated with disease recurrence. Using bioinformatics, we also discovered that miR-106b-25 may specifically influence focal adhesion-related pathways. This observation was experimentally confirmed using miR-106b-25-transduced 22Rv1 human prostate cancer cells. After infection with a miR-106b-25 lentiviral expression construct, 22Rv1 cells showed increased adhesion to basement membrane- and bone matrix-related filaments and enhanced soft agar growth. In summary, miR-106b-25 was found to be associated with prostate cancer progression and metastasis and may do so by altering apoptosis- and focal adhesion-related pathways. To elucidate the effects miR-106b, we up-regulated miR-106b in LNCaP cells and examined gene expression alterations on a global scale with Affymetrix arrays.
2012-05-01 | GSE34893 | GEO
Project description:We and others previously reported that the miR-106b-25 microRNA cluster is a candidate oncogene in human prostate cancer. Here, we made the novel observation that miR-106b-25 expression is further up-regulated in distant metastasis. Moreover, increased tumor miR-106b expression was associated with early disease recurrence. To identify yet unknown oncogenic functions of the prognostic miR-106b, we overexpressed it in LNCaP human prostate cancer cells to examine miR-106b-induced global expression changes among protein-coding genes. The approach revealed that caspase-7 is a candidate direct target of miR-106b, which was confirmed by Western blot analysis and a 3M-bM-^@M-^YUTR reporter assay. Other analyses showed that caspase-7 is down-regulated in primary human prostate tumors and metastatic lesions across multiple datasets and is by itself associated with disease recurrence. Using bioinformatics, we also discovered that miR-106b-25 may specifically influence focal adhesion-related pathways. This observation was experimentally confirmed using miR-106b-25-transduced 22Rv1 human prostate cancer cells. After infection with a miR-106b-25 lentiviral expression construct, 22Rv1 cells showed increased adhesion to basement membrane- and bone matrix-related filaments and enhanced soft agar growth. In summary, miR-106b-25 was found to be associated with prostate cancer progression and metastasis and may do so by altering apoptosis- and focal adhesion-related pathways. To elucidate the effects miR-106b, we up-regulated miR-106b in LNCaP cells and examined gene expression alterations on a global scale with Affymetrix arrays. LNCaP cells were transfected with pre-miR oligos and 24 hr post-transfection total RNA was collected for microarray anaylsis.
2012-04-30 | E-GEOD-34893 | biostudies-arrayexpress