Gastrodin promotes CNS myelination via a lncRNA Gm7237/miR-142a/MRF pathway.
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ABSTRACT:
SUBMITTER: Shu Y
PROVIDER: S-EPMC8354603 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
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Project description:Background:The mortality and morbidity rates of pancreatic adenocarcinoma have been increasing over the past two decades, and an understanding of the mechanisms underlying pancreatic adenocarcinoma progression is urgently needed. The long non-coding RNA ZFAS1 has been demonstrated to be an oncogene in some cancers, but its function and mechanism in pancreatic adenocarcinoma remain unclear. Methods:The ZFAS1 expression level in pancreatic adenocarcinoma was predicted by bioinformatic analysis, and the expression level of ZFAS1 in pancreatic adenocarcinoma tissue samples and cell lines was further detected by quantitative real-time PCR and in situ hybridization. The functions of ZFAS1 in pancreatic adenocarcinoma in vitro and in vivo were investigated by further bioinformatic analysis. Dual-luciferase reporter assays were used to confirm the binding of ZFAS1/miR-3924 and miR-3924/ROCK2, and rescue assays were performed to further investigate the underlying mechanism. Results:ZFAS1 overexpression in pancreatic adenocarcinoma was predicted and experimentally verified. ZFAS1 silencing inhibited pancreatic adenocarcinoma metastasis in vitro and in vivo. The competing endogenous RNA mechanism of ZFAS1 was also identified. Conclusions:Our results demonstrated the promotive effect of ZFAS1 on pancreatic adenocarcinoma metastasis and suggested its potential role as a novel regulator of ROCK2.
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Project description:microRNA-489 (miR-489) is a novel cancer-related miRNAs and functions as a tumor suppressor in human cancers. While, the clinical significance of miR-489 and its role in colorectal cancer (CRC) remain rarely known. Here, we found that the levels of miR-489 in CRC tissues were significantly lower than those in matched tumor-adjacent tissues. Furthermore, decreased levels of miR-489 also observed in CRC cell lines compared to HIEC cells. Clinicopathological analysis revealed that miR-489 underexpression was positively correlated with advanced pT stage, pN stage and AJCC stage. Moreover, miR-489 low expressing CRC patients showed a obvious shorter survival. Functionally, miR-489 restoration inhibited cell migration and invasion as well as epithelial-mesenchymal transition (EMT) in HCT116 cells, while miR-489 loss facilitated these cellular processes in SW480 cells. In vivo experiments revealed that miR-489 overexpression reduced the number of metastatic nodules in nude mice liver. Notably, TWIST1 was recognized as a direct downstream target of miR-489 in CRC cells. Interestingly, TWIST1 restoration abrogated the effects of miR-489 on CRC cells with enhanced cell migration, invasion and EMT process. Furthermore, overexpression of long noncoding RNA cardiac hypertrophy-related factor (lncRNA CHRF) was inversely correlated with miR-489 expression in CRC tissues. CHRF knockdown increased the expression of miR-489 and suppressed EMT events of HCT116 cells, while CHRF overexpression showed opposite effects on miR-489 expression and EMT in SW480 cells. Taken together, this work support the first evidence that lncRNA CHRF-induced miR-489 loss facilitates metastasis and EMT process of CRC cells probably via TWIST1/EMT signaling pathway.
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Project description:microRNAs (miRNAs) have been implicated in oligodendrogenesis and demyelinating diseases; however, identification of individual miRNAs responsible has remained elusive. Through targeted mutagenesis, we find that miR-219 is required for proper oligodendrocyte differentiation and myelination in vivo. Deletion of miR-338 together with miR-219 further exacerbates hypomyelination phenotypes. Temporally specific ablation reveals a critical role for miR-219 in oligodendrocyte remyelination after demyelination, while overexpression of miR-219 promotes precocious oligodendrocyte maturation and myelin regeneration. Accordingly, administration of miR-219 mimics to lysolecithin-induced demyelinating lesions in the murine spinal cord and brain enhances myelin restoration. Through integrating analyses of transcriptome profiling and biotin-affinity miRNA pull-down, we identify a set of stage-specific targets of miR-219, including Etv5 and Lingo1, as oligodendrocyte differentiation inhibitors. Inhibiting Etv5 and Lingo1 leads to a partial rescue of differentiation defects observed in miR-219-mutant OLs in vitro. Together, our findings identify context-specific miRNA-regulated checkpoints that control CNS myelinogenesis and myelin repair.
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Project description:Long noncoding RNAs (lncRNAs) exert significant roles at transcriptional and post-transcriptional levels. Stem cells from apical papilla (SCAPs) differentiate into dentin/bone-like tissues under certain conditions. So far, whether lncRNA-H19 can affect the proliferative behaviors and osteo/odontogenesis of SCAPs, as well as its specific mechanism remain to be elucidated. Here, SCAPs were isolated and transfected with the lentiviruses or packaging vectors. Our results showed that lncRNA-H19 had no significant effect on the proliferative behaviors of SCAPs, as presented by CCK-8 assay, EdU assay and flow cytometry (FCM). Furthermore, alkaline phosphatase (ALP) activity, alizarin red staining, Western blot assay (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and in vivo bone formation assay were conducted to verify the biological influences of H19 on SCAPs. Overexpression of H19 led to the enhanced osteo/odontogenesis of SCAPs, whereas knockdown of H19 inhibited these effects. Mechanistically, H19 competitively bound to miR-141 and prevented SPAG9 from miRNA-mediated degradation, thus significantly elevating phosphorylated levels of p38 and JNK and facilitating the committed differentiation of SCAPs. Taken together, the osteo/odontogenesis of SCAPs was upregulated by overexpression of H19 via miR-141/SPAG9 pathway.
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Project description:Noncoding RNA (ncRNA) is involved in the occurrence, development, metastasis, and drug resistance of tumors and involves a variety of biological functions. In addition, miRNA can regulate proliferation and migration and even regulate epigenetics to promote the development of multiple myeloma (MM). However, the mechanism of ncRNA involved in MM is still unclear, and there are many unknown ncRNAs to be explored. This research is aimed at discovering the unknown lncRNA in MM through high-throughput sequencing and to study the mechanism and role of competitive endogenous RNA (ceRNA) involved in the pathogenesis of MM for the development of novel molecular markers and potential new targeted drugs. We screened out 262 new lncRNAs with statistical differences by RNA sequencing and selected the lncRNA MSTRG.29039.1 according to the expression and function of lncRNAs and their target genes in MM. We verified that MSTRG.29039.1 and its target gene OSMR were highly expressed in MM. After knockdown of MSTRG.29039.1 in MM cell lines, the expression of OSMR was decreased, and the expression of hsa-miR-12119 was upregulated which can also promote cell apoptosis and inhibit proliferation. Then, we knocked down hsa-miR-12119 and MSTRG.29039.1, we found that apoptosis of MM cells was reduced, and cell proliferation was increased compared with just knocking down hsa-miR-12119. We further verified the direct binding relationship between MSTRG.29039.1 and OSMR by the dual-luciferase reporter assay system. Thus, MSTRG.29039.1 can competitively bind with miRNA to counteract the inhibitory effect of miRNA on OSMR, which regulates cell proliferation and apoptosis through the JAK2/STAT3 pathway. In a conclusion, lncRNA MSTRG.29039.1 could promote proliferation by sponging hsa-miR-12119 via the JAK2/STAT3 pathway in multiple myeloma. This may be a molecular marker and a potential therapeutic target for MM.
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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC), a subtype of pancreatic cancer, is a malignant tumor with unfavorable prognosis. Despite accumulating researches have made efforts on finding novel therapeutic methods for this disease, the underlying mechanism of long non-coding RNAs (lncRNAs) remains elusive. OIP5 antisense RNA 1 (OIP5-AS1) has been reported to play important role in the occurrence and development of multiple human cancers. This study was aimed at unveiling the regulatory role of OIP5-AS1 in PDAC.MethodsRT-qPCR analysis revealed the OIP5-AS1 expression in PDAC tissues and adjacent normal ones. Kaplan-Meier method was applied to analyze the overall survival of patients with high or low level of OIP5-AS1. Gain- or loss-of function assays were performed to assess the effects of OIP5-AS1 knockdown on cell functions, including proliferation, migration and EMT process. Mechanism experiments, such as luciferase reporter and RNA pull-down assays proved the interaction between OIP5-AS1 and miR-429 as well as that between miR-429 and FOXD1.ResultsOIP5-AS1 was up-regulated in PDAC tissues and cell lines, and high level of OIP5-AS1 indicated poor prognosis in PDAC patients. OIP5-AS1 knockdown hindered cell proliferation, migration and epithelial-mesenchymal transition (EMT) process, while overexpression of OIP5-AS1 caused the opposite results. OIP5-AS1 activated ERK pathway through up-regulating forkhead box D1 (FOXD1) expression by sponging miR-429. Furthermore, OIP5-AS1 facilitated cell growth in vivo.ConclusionOIP5-AS1 exerted oncogenic function in PDAC cells through targeting miR-429/FOXD1/ERK pathway.
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