Downregulation of long non-coding RNA Opa interacting protein 5-antisense RNA 1 inhibits breast cancer progression by targeting sex-determining region Y-box 2 by microRNA-129-5p upregulation.
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ABSTRACT:
SUBMITTER: Zeng H
PROVIDER: S-EPMC6317922 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundBreast cancer is the leading cause of cancer-related mortality in women worldwide. Long non-coding RNAs (lncRNAs) are of critical importance in tumor drug resistance. Herein, this study aims to determine the roles of lncRNA ZEB1-AS1 in drug resistance of breast cancer involving microRNA-129-5p (miR-129-5p) and ZEB1.MethodsMicroarray-based gene expression profiling of breast cancer was conducted to identify the differentially expressed lncRNAs. ZEB1 expression was measured in adjacent and cancerous tissues. Next, MCF-7 and MDA-MB-231 cells were treated with a series of inhibitor, mimic or siRNA to clarify the roles of lncRNA ZEB1-AS1 and miR-129-5p in drug resistance of breast cancer. Then the target relationship of miR-129-5p with lncRNA ZEB1-AS1 and ZEB1 was verified. The expression patterns of miR-129-5p, lncRNA ZEB1-AS1, Bcl-2, MDR-1, ZEB1 and corresponding proteins were evaluated. Moreover, the apoptosis and drug resistance of MCF-7 cell were detected by CCK-8 and flow cytometry respectively.ResultsLncRNA ZEB1-AS1 was observed to be an upregulated lncRNA in breast cancer, and ZEB1 overexpression was noted in breast cancerous tissues. MiR-129-5p was revealed to specifically bind to both ZEB1 and lncRNA ZEB1-AS1. Moreover, the expression levels of ZEB1-AS1, ZEB1, Bcl-2, MDR-1, and corresponding proteins were decreased, but the expression of miR-129-5p was increased with transfection of miR-129-5p mimic and lncRNA ZEB1-AS1 siRNA. Besides, drug resistance to cisplatin was inhibited, and cell apoptosis was promoted in breast cancer after transfection of miR-129-5p mimic, lncRNA ZEB1-AS1 siRNA, and ZEB1 siRNA.ConclusionIn conclusion, the study provides evidence that lncRNA ZEB1-AS1 silencing protects against drug resistance in breast cancer by promoting miR-129-5p-dependent ZEB1 downregulation. It may serve as a novel therapeutic target in breast cancer treatment.
| S-EPMC7092489 | biostudies-literature
Project description:Breast cancer brain metastases (BCBMs) have been underinvestigated despite their high incidence and poor outcome. MicroRNAs (miRNAs), and particularly circulating miRNAs, regulate multiple cellular functions, and their deregulation has been reported in different types of cancer and metastasis. However, their signature in plasma along brain metastasis development and their relevant targets remain undetermined. Here, we used a mouse model of BCBM and next-generation sequencing (NGS) to establish the alterations in circulating miRNAs during brain metastasis formation and development. We further performed bioinformatics analysis to identify their targets with relevance in the metastatic process. We additionally analyzed human resected brain metastasis samples of breast cancer patients for target expression validation. Breast cancer cells were injected in the carotid artery of mice to preferentially induce metastasis in the brain, and samples were collected at different timepoints (5 h, 3, 7, and 10 days) to follow metastasis development in the brain and in peripheral organs. Metastases were detected from 7 days onwards, mainly in the brain. NGS revealed a deregulation of circulating miRNA profile during BCBM progression, rising from 18% at 3 days to 30% at 10 days following malignant cells' injection. Work was focused on those altered prior to metastasis detection, among which were miR-802-5p and miR-194-5p, whose downregulation was validated by qPCR. Using targetscan and diana tools, the transcription factor myocyte enhancer factor 2C (MEF2C) was identified as a target for both miRNAs, and its expression was increasingly observed in malignant cells along brain metastasis development. Its upregulation was also observed in peritumoral astrocytes pointing to a role of MEF2C in the crosstalk between tumor cells and astrocytes. MEF2C expression was also observed in human BCBM, validating the observation in mouse. Collectively, downregulation of circulating miR-802-5p and miR-194-5p appears as a precocious event in BCBM and MEF2C emerges as a new player in brain metastasis development.
| S-EPMC7053247 | biostudies-literature
Project description:BackgroundThe peroxisome proliferator-activated receptor γ (PPARγ) promotes autophagy and regulates the inflammatory response. However, the effects of the PPARγ on inflammation in acute respiratory distress syndrome (ARDS) are unclear. This study sought to explore the mechanism by which the downregulation of microRNA-129-5p (miR-129-5p) attenuates the inflammatory response in ARDS patients by regulating PPARγ-mediated autophagy.MethodsLipopolysaccharide (LPS) was used to establish an acute lung injury (ALI) mice model to simulate ARDS. GW9662 and pioglitazone were applied to inhibit and activate the PPARγ, respectively. Enzyme-linked immunoassays were used to detect inflammatory cytokines. The expressions of miR-129-5p, the PPARγ, and the autophagy-marker protein were detected by quantitative polymerase chain reaction (qPCR) or Western blot. Dual-luciferase reporter assays were used to verify the targeting relationship between miR-129-5p and PPARγ messenger RNA (mRNA). Human lung epithelial cells BEAS-2B transfected with the miR-129-5p inhibitor and/or the short interfering RNA PPARγ (si-PPARγ) were applied to explore the mechanism.ResultsThe results showed that pioglitazone promoted autophagy and relieved lung injury caused by LPS, while GW9662 exacerbated lung injury. MiR-129-5p directly targeted the PPARγ. Inhibiting the expression of miR-129-5p increased the level of the PPARγ, induced autophagy, and inhibited apoptosis and the inflammatory response. Conversely, silencing the PPARγ had the opposite effects, and blocked the protective effects of the miR-129-5p inhibitor.ConclusionsThe inhibition of miR-129-5p may induce autophagy and inhibit the inflammatory response by promoting the expression of the PPARγ, thereby relieving ARDS.
| S-EPMC9011209 | biostudies-literature
Project description:The ubiGmccBA operon of Clostridium acetobutylicum is involved in methionine to cysteine conversion. We showed that its expression is controlled by a complex regulatory system combining several RNA-based mechanisms. Two functional convergent promoters associated with transcriptional antitermination systems, a cysteine-specific T-box and an S-box riboswitch, are located upstream of and downstream from the ubiG operon, respectively. Several antisense RNAs were synthesized from the downstream S-box-dependent promoter, resulting in modulation of the level of ubiG transcript and of MccB activity. In contrast, the upstream T-box system did not appear to play a major role in regulation, leaving antisense transcription as the major regulatory mechanism for the ubiG operon. The abundance of sense and antisense transcripts was inversely correlated with the sulfur source availability. Deletion of the downstream promoter region completely abolished the sulfur-dependent control of the ubiG operon, and the expression of antisense transcripts in trans did not restore the regulation of the operon. Our data revealed important insights into the molecular mechanism of cis-antisense-mediated regulation, a control system only rarely observed in prokaryotes. We proposed a regulatory model in which the antisense RNA controlled the expression of the ubiG operon in cis via transcriptional interference at the ubiG locus.
| S-EPMC2566862 | biostudies-other
Project description:Obesity is an epidemic matter increasing risk for cardiovascular diseases and metabolic disorders such as type 2 diabetes. We recently examined the association between visceral fat adiposity and gene expression profile of peripheral blood cells in human subjects. In a series of studies, Opa (Neisseria gonorrhoeae opacity-associated)-interacting protein 5 (OIP5) was nominated as a molecule of unknown function in adipocytes and thus the present study was performed to investigate the role of OIP5 in obesity. Adenovirus overexpressing Oip5 (Ad-Oip5) was generated and infected to 3T3-L1 cells stably expressing Coxsackie-Adenovirus Receptor (CAR-3T3-L1) and to mouse subcutaneous fat. For a knockdown experiment, siRNA against Oip5 (Oip5-siRNA) was introduced into 3T3-L1 cells. Proliferation of adipose cells was measured by BrdU uptake, EdU-staining, and cell count. Significant increase of Oip5 mRNA level was observed in obese white adipose tissues and such increase was detected in both mature adipocytes fraction and stromal vascular cell fraction. Ad-Oip5-infected CAR-3T3-L1 preadipocytes and adipocytes proliferated rapidly, while a significant reduction of proliferation was observed in Oip5-siRNA-introduced 3T3-L1 preadipocytes. Fat weight and number of adipocytes were significantly increased in Ad-Oip5-administered fat tissues. Oip5 promotes proliferation of pre- and mature-adipocytes and contributes adipose hyperplasia. Increase of Oip5 may associate with development of obesity.
| S-EPMC3916335 | biostudies-literature
Project description:Osteoporosis is a frequently occurring bone disease in middle-aged and aged men and women. However, current therapies on this disease are still not ideal. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNA with a length of 18-25 nucleotides. miRNAs have been identified as important regulators for development, metabolism, carcinogenesis, and bone formation. miR-129-5p has been reported as a regulator of cancer and neuroscience, whereas studies about its function on bone formation is still limited. In this study, we investigated the function and mechanism of miR-129-5p on osteoblast differentiation and bone formation. We have assessed the expression of miRNAs in bone mesenchymal stem cells from aging and menopause osteoporosis C57BL6 mice. The expression of miR-129-5p was altered in all osteoporosis models. Besides, the expression of miR-129-5p was negatively correlated with osteoblastic differentiation markers in the femur tissues of C57BL/6 mice of different ages. We further demonstrated that overexpression of miR-129-5p inhibited osteoblast differentiation in MC3T3-E1 cell line, as well as bone formation of C57BL/6 mice. On the other hand, down-regulation of miR-129-5p enhanced osteoblast differentiation and bone formation. We also found that miR-129-5p inhibited Wnt/β-catenin pathway in osteoblast. The target gene of miR-129-5p has been forecasted and proved as Tcf4. We further found that plasmid containing Tcf4-3' UTR sequence enhanced osteoblast differentiation, as well as Wnt/β-catenin pathway in MC3T3-E1 cells. To further investigate the rescue effect of miR-129-5p inhibitor, we manufactured bioengineered novel recombinant miR-129-5p inhibitor through Escherichia coli system and then tested its function. The results showed that the novel recombinant miR-129-5p inhibitor promoted osteoblast differentiation and greatly ameliorated menopause osteoporosis in C57BL6 mice. In conclusion, we have discovered miR-129-5p as an inhibitor of bone formation. miR-129-5p inhibited downstream transcription factors of Wnt/β-catenin pathway through targeting Tcf4. Moreover, novel recombinant miR-129-5p inhibitor showed rescue effect on osteoporosis. This study has revealed a new mechanism of osteogenic differentiation and provided novel therapeutic strategies for treatment of skeletal disorders.
| S-EPMC7681249 | biostudies-literature
Project description:Box C/D snoRNAs are known to guide site-specific ribose methylation of ribosomal RNA. Here, we demonstrate a novel and unexpected role for box C/D snoRNAs in guiding 18S rRNA acetylation in yeast. Our results demonstrate, for the first time, that the acetylation of two cytosine residues in 18S rRNA catalyzed by Kre33 is guided by two orphan box C/D snoRNAs-snR4 and snR45 -not known to be involved in methylation in yeast. We identified Kre33 binding sites on these snoRNAs as well as on the 18S rRNA, and demonstrate that both snR4 and snR45 establish extended bipartite complementarity around the cytosines targeted for acetylation, similar to pseudouridylation pocket formation by the H/ACA snoRNPs. We show that base pairing between these snoRNAs and 18S rRNA requires the putative helicase activity of Kre33, which is also needed to aid early pre-rRNA processing. Compared to yeast, the number of orphan box C/D snoRNAs in higher eukaryotes is much larger and we hypothesize that several of these may be involved in base-modifications.
| S-EPMC5464676 | biostudies-literature
Project description:Background: The role of serum extracellular vesicles (EVs) is less known in psoriasis. Objectives: To explore the transcriptomic profile of serum EVs and the potential biomarkers in psoriasis. Methods: EVs were isolated by differential ultracentrifugation and identified by transmission electron microscope. The diameters of EVs were detected using nanoparticle tracking analysis. Serum EVs-keratinocyte interaction was observed through confocal fluorescence microscopy. miRNA microarray and mRNA microarray were performed in serum EVs (n = 4) and skin lesions (n = 3), respectively. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization were used to detect the expression of miRNAs in serum EVs and skin lesions (n = 15). Bioinformatics analysis was performed to predict the potential target genes and functions of miR-1305 and miR-6785-5p. Western blot, CCK-8 and enzyme-linked immunosorbent assay (ELISA) were used to detect the EVs' biomarkers, keratinocytes proliferation and cytokines secretion. Results: A total of 16 miRNAs and 1,725 mRNAs were significantly dysregulated in serum EVs and skin lesions, respectively. miR-1305 was down-regulated and miR-6785-5p was upregulated in both serum EVs and skin lesions. Serum EVs could be taken up by keratinocytes. miR-1305 was downregulated and miR-6785-5p were upregulated in keratinocytes after co-cultured with psoriasis serum EVs compared with controls. Psoriasis serum EVs promoted keratinocyte proliferation and the secretion of CCL20 and IL-8. Serum EVs miR-1305 and miR-6785-5p were associated with disease severity. Conclusion: Serum EVs might be involved in the activation of keratinocytes through loaded miRNAs in psoriasis. Serum EVs miR-1305 and miR-6785-5p may be associated with psoriasis.
| S-EPMC9399421 | biostudies-literature
Project description:To identify potential molecular targets for diagnosis, treatment and/or prevention of lung and esophageal carcinomas, we screened for genes that were overexpressed in tumors through gene expression analyses of 120 lung cancers and 19 esophageal squamous-cell carcinomas using a cDNA microarray consisting of 27,648 cDNA or expressed sequence tags. In this process, we identified a gene, Opa interacting protein 5 (OIP5), to be highly transactivated in the majority of lung and esophageal cancers. Immunohistochemical staining using 336 archived non-small cell lung cancers and 305 esophageal squamous-cell carcinomas specimens demonstrated that OIP5 expression was significantly associated with poor prognosis of lung and esophageal cancer patients (P = 0.0053 and 0.0168, respectively), and multivariate analysis confirmed its independent prognostic value for non-small cell lung cancers (P = 0.0112). Suppression of OIP5 expression with siRNA effectively suppressed the growth of cancer cells, whereas the exogenous expression of OIP5 enhanced the growth of cancer cells. In addition, OIP5 protein is likely to be stabilized through its interaction with Raf1. OIP5 is a promising target for developing new prognostic biomarkers and anti-cancer drugs.
| S-EPMC7713625 | biostudies-literature
Project description:Sex-determining region Y-box 9 (SOX9), a vital transcription factor, play important roles in numerous biological and pathological processes. However, the clinical significance and biological role of SOX9 expression has not been characterized in human esophageal squamous cell cancer (ESCC). Herein, we found that SOX9 was markedly upregulated, at both mRNA and protein level, in ESCC cell lines and ESCC tissues and that SOX9 expression was significantly correlated with tumor clinical stage, T classification, N classification, M classification, pathological differentiation, and shorter overall survival. The proliferation and tumorigenicity of ESCC cells were dramatically induced by SOX9 overexpression but were inhibited by SOX9 knockdown both in vitro and in vivo. Moreover, we demonstrated that upregulation of SOX9 increased the expression of phosphorylated Akt, the cyclin-dependent kinase (CDK) regulator cyclin D1, phosphorylated forkhead box O (FOXO)1, and phosphorylated FOXO3, but SOX9 downregulation decreased their expression, whereas the levels of the CDK inhibitors p21Cip1 and p27Kip1 were attenuated in SOX9-transduced cells. Taken together, our results suggest that SOX9 plays an important role in promoting the proliferation and tumorigenesis of ESCC and may represent a novel prognostic marker for the disease.
| S-EPMC4741601 | biostudies-literature