P422: TARGETING THE WT1MUT-MIR-193A TRANSCRIPTIONAL AXIS WITH INT-1B3, A NOVEL LIPID NANOPARTICLE-FORMULATED MIR-193A-3P MIMIC IN ACUTE MYELOID LEUKEMIA
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ABSTRACT:
SUBMITTER: Yang X
PROVIDER: S-EPMC10428817 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:Emerging data show that microRNA 193a-3p (miR-193a-3p) has a suppressive role in many cancers and is often downregulated in tumors, as compared to surrounding normal tissues. Therefore, mimics of miR-193a-3p could be used as an attractive therapeutic approach in oncology. To better understand and document the molecular mechanism of action of 1B3, a novel synthetic miRNA-193a-3p mimic, RNA sequencing was performed after transfection of 1B3 in six different human tumor cell lines. Genes differentially expressed (DE) in at least three cell lines were mapped by Ingenuity Pathway Analysis (IPA), and interestingly, these results strongly indicated upregulation of the tumor-suppressive phosphatase and tensin homolog (PTEN) pathway, as well as downregulation of many oncogenic growth factor signaling pathways. Importantly, although unsurprisingly, IPA identified miR-193a-3p as a strong upstream regulator of DE genes in an unbiased manner. Furthermore, biological function analysis pointed to an extensive link of 1B3 with cancer, via expected effects on tumor cell survival, proliferation, migration, and cell death. Our data strongly suggest that miR-193a-3p/1B3 is a potent tumor suppressor agent that targets various key oncogenic pathways across cancer types. Therefore, the introduction of 1B3 into tumor cells may represent a promising strategy for cancer treatment.
| S-EPMC7896128 | biostudies-literature
Project description:Compelling evidence demonstrates that miR-193a-3p is a tumor suppressor microRNA in many cancer types, and its reduced expression is linked to cancer initiation and progression, metastasis, and therapy resistance. However, its mechanism of action is not consistently described between studies, and often contradicts the pleiotropic role of a microRNA in manipulating several different mRNA targets. We therefore comprehensively investigated miRNA-193a-3p's mode of action in a panel of human cancer cell lines, with a variety of genetic backgrounds, using 1B3, a synthetic microRNA mimic. Interestingly, the exact mechanism through which 1B3 reduced cell proliferation varied between cell lines. 1B3 efficiently reduced target gene expression, leading to reduced cell proliferation/survival, cell cycle arrest, induction of apoptosis, increased cell senescence, DNA damage, and inhibition of migration. SiRNA silencing of 1B3 target mRNAs further highlighted the advantage of the pleiotropic mechanism of 1B3 action, as repression of individual targets did not achieve the same robust effect on cell proliferation in all cell lines. Importantly, a novel lipid nanoparticle-based formulation of 1B3, INT-1B3, demonstrated marked anti-tumor activity as a single agent following systemic administration in tumor-bearing mice. Together, these data strongly support the development of 1B3 as a novel therapeutic agent for treatment of human cancer.
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Project description:Long intergenic non-coding RNA 00152 (LINC00152) is aberrantly expressed in various human malignancies and plays an important role in the pathogenesis. Here, we found that LINC00152 is upregulated in hepatocellular carcinoma (HCC) tissues as compared to adjacent non-neoplastic tissues; gain-and-loss-of-function analyses in vitro showed that LINC00152 facilitates HCC cell cycle progression through regulating the expression of CCND1. LINC00152 knockdown inhibits tumorigenesis in vivo. MS2-RIP analysis indicated that LINC00152 binds directly to miR-193a/b-3p, as confirmed by luciferase reporter assays. Furthermore, ectopic expression of LINC00152 partially halted the decrease in CCND1 expression and cell proliferation capacity induced by miR-193a/b-3p overexpression. Thus, LINC00152 acts as a competing endogenous RNA (ceRNA) by sponging miR-193a/b-3p to modulate its target gene, CCND1. Our findings establish a ceRNA mechanism regulating cell proliferation in HCC via the LINC00152/miR-193a/b-3p/CCND1 signalling axis, and identify LINC00152 as a potential therapeutic target for HCC.
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Project description:Congenital heart disease (CHD) is the most common noninfectious cause of death during the neonatal stage. T-box transcription factor 1 (TBX1) is the main genetic determinant of 22q11.2 deletion syndrome (22q11.2DS), which is a common cause of CHD. Moreover, ferroptosis is a newly discovered kind of programmed cell death. In this study, the interaction among TBX1, miR-193a-3p, and TGF-β2 was tested using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and dual-luciferase reporter assays. TBX1 silencing was found to promote TGF-β2 messenger ribonucleic acid (mRNA) and protein expression by downregulating the miR-193a-3p levels in H9c2 cells. In addition, the TBX1/miR-193a-3p/TGF-β2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe2+ concentrations, mitochondrial ROS levels, and malondialdehyde (MDA) contents; Cell Counting Kit-8 (CCK-8) assays and transmission electron microscopy; and Western blotting analysis of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), NADPH oxidase 4 (NOX4), and acyl-CoA synthase long-chain family member 4 (ACSL4) protein expression. The protein expression of NRF2, GPX4, HO-1, NOX4, and ACSL4 and the level of MDA in human CHD specimens were also detected. In addition, TBX1 and miR-193a-3p expression was significantly downregulated and TGF-β2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-β2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-β2 may be a target gene for CHD diagnosis and treatment in children.
| S-EPMC8759832 | biostudies-literature
Project description:Substrate topographical features induce osteogenic differentiation of bone marrow stem cells (BMSCs), but the underlying mechanisms are unclear. As microRNAs (miRNAs) play key roles in osteogenesis and bone regeneration, it would be meaningful to elucidate the roles of miRNAs in the intracellular signaling cascade of topographical cue-induced osteogenic differentiation. In this study, the miRNA expression profile of the topographical feature-induced osteogenic differentiation group is different from that of the chemical-factors-induced osteogenic differentiation group. miR-193a-3p is sensitive to substrate topographical features and its downregulation enhances osteogenic differentiation only in the absence of osteogenesis-inducing medium. Also, substrate topographical features specifically activate a nonclassical osteogenetic pathway-the mitogen-activated protein kinase (MAPK) pathway. Loss- and gain-of-function experiments demonstrate that miR-193a-3p regulates the MAPK pathway by targeting the MAP3k3 gene. In conclusion, this data indicates that different osteogenic-lineage-related intracellular signaling cascades are triggered in BMSCs subjected to biophysical or chemical stimulation. Moreover, the miR-193a-3p-MAP3k3 signaling axis plays a pivotal role in the transduction of biophysical cues from the substrate to regulate the osteogenic lineage specification of BMSCs, and hence may be a promising molecular target for bone regenerative therapies.
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Project description:Chordomas are low-grade malignancies accounting for 1-4% of primary bone malignancies. Moreover, local recurrences increase the rate of metastasis. Our previous study identified the far upstream element (FUSE)-binding protein 1 (FUBP1) as a biomarker and potential therapeutic target for chordoma. In this study, lncRNA KRT8P41 was identified as a lncRNA positively correlated with FUBP1. In chordoma patients, higher lncRNA KRT8P41 expression was correlated with a poorer prognosis. LncRNA KRT8P41 silencing significantly inhibited chordoma cell proliferation and invasion. miR-193a was negatively correlated with lncRNA KRT8P41 and FUBP1; lncRNA KRT8P41 inhibited miR-193a expression, and miR-193a inhibited FUBP1 expression. Furthermore, miR-193a directly bound to lncRNA KRT8P41 and FUBP1 and lncRNA KRT8P41 competed with FUBP1 for miR-193a binding and relieved miR-193a-mediated FUBP1 inhibition. LncRNA KRT8P41 silencing inhibited, whereas miR-193a inhibition promoted chordoma cell proliferation and invasion; the inhibition of miR-193a attenuated the roles of lncRNA KRT8P41. Within chordoma tissues, the expression of miR-193a was decreased, and the expression of FUBP1 increased compared to normal control tissues. LncRNA KRT8P41 exhibited a positive correlation with FUBP1 and a negative correlation with miR-193a in vivo. Therefore, it was concluded that lncRNA KRT8P41, miR-193a-3p, and FUBP1 form a lncRNA-miRNA-mRNA axis, modulating the proliferation and invasion of chordoma cells.
| S-EPMC8529087 | biostudies-literature
Project description:Lung adenocarcinoma (LUAD) remains the most common subtype of lung malignancy. Cuproptosis is a newly identified cell death which could regulate tumor cell proliferation and progression. Long non-coding RNAs (lncRNAs) are key molecules and potential biomarkers for diagnosing and treating various diseases. However, the effects of cuproptosis-related lncRNAs on LUAD are still unclear. In our study, 7 cuproptosis-related lncRNAs were selected to establish a prognostic model using univariate Cox regression analysis, LASSO algorithm, and multivariate analysis. Furthermore, we evaluated AC008764.2, AL022323.1, ELN-AS1, and LINC00578, which were identified as protective lncRNAs, while AL031667.3, AL606489.1, and MIR31HG were identified as risk lncRNAs. The risk score calculated by the prognostic model proved to be an effective independent factor compared with other clinical features by Cox regression analyses [univariate analysis: hazard ratio (HR) = 1.065, 95% confidence interval (CI) = 1.043-1.087, P < 0.001; multivariate analysis: HR = 1.067, 95% CI = 1.044-1.091, P < 0.001]. In addition, both analyses (ROC and nomogram) were used to corroborate the accuracy and reliability of this signature. The correlation between cuproptosis-related lncRNAs and immune microenvironment was elucidated, where 7 immune cells and 8 immune-correlated pathways were found to be differentially expressed between two risk groups. Furthermore, our results also identified and verified the ceRNA of cuproptosis-related lncRNA MIR31HG/miR-193a-3p/TNFRSF21 regulatory axis using bioinformatics tools. MIR31HG was highly expressed in LUAD specimens and some LUAD cell lines. Inhibition of MIR31HG clearly reduced the proliferation, migration, and invasion of the LUAD cells. MIR31HG showed oncogenic features via sponging miR-193a-3p and tended to positively regulate TNFRSF21 expression. In a word, lncRNA MIR31HG acts as an oncogene in LUAD by targeting miR-193a-3p to modulate TNFRSF21, which may be beneficial to the gene therapy of LUAD.
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Project description:Our purpose is to verify that miR-146b-3p targets the downstream transcript TNFAIP2 in order to reveal the machinery underlying the miR-146b-3p/TNFAIP2 axis regulating acute myeloid leukaemia (AML) differentiation. Bioinformatics analyses were performed using multiple databases and R packages. The CD11b+ and CD14+ cell frequencies were detected using flow cytometry and immunofluorescence staining. The TNFAIP2 protein expression was evaluated using western blotting, immunocytochemistry and immunofluorescence staining. The qRT-PCR was conducted to detect the expression of TNFAIP2 and miR-146b-3p. TNFAIP2 and its correlated genes were enriched in multiple cell differentiation pathways. TNFAIP2 was upregulated upon leukaemic cell differentiation. miR-146b-3p directly targeted TNFAIP2, resulting in a decrease in TNFAIP2 expression. Forced expression of TNFAIP2 or knockdown of miR-146b-3p significantly induced the differentiation of MOLM-13 cells. In this study, we demonstrated that TNFAIP2 is a critical driver in inducing differentiation and that the miR-146b-3p/TNFAIP2 axis involves in regulating cell differentiation in AML.
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Project description:Epithelial-mesenchymal transition (EMT) is an early and key process in the metastatic cascade during the progression of colorectal cancer (CRC). The aim of the present study was to identify deregulated EMT-related microRNAs (miRNAs/miRs) of CRC and assess the effect of differentially expressed miRNAs on the prognosis of patients with CRC. Genome-wide expression profiling of miRNAs was assessed in 3 EMT-negative and 3 EMT-positive CRC tissues. Differentially expressed miRNA was further validated in 90 pairs of CRC and corresponding paracarcinoma tissues using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 6 miRNAs (miR-10a-5p miR-204-3p, miR-1224-3p, miR-193a-3p, miR-365a-3p and miR-3678-3p) were identified to be differentially expressed between different EMT statuses of CRC tissues. Following validation using RT-qPCR, 3 miRNAs (miR-10a-5p, miR-365a-3p and miR-193a-3p) were selected for subsequent studies. The expression levels of miR-10a-5p, miR-193a-3p and miR-365a-3p were markedly increased compared with levels in corresponding paracarcinoma tissues. Survival analyses revealed that down-regulation of miR-193a-3p was associated with worse prognosis of patients with CRC, particularly in female and older patients. The results of the present study indicate that miR-193a-3p may be an EMT-related biomarker and serve as a novel prognostic factor for CRC.
| S-EPMC5494605 | biostudies-other
Project description:Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.
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