A Schistosoma japonicum MicroRNA Exerts Antitumor Effects Through Inhibition of Both Cell Migration and Angiogenesis by Targeting PGAM1.
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ABSTRACT:
SUBMITTER: Hu C
PROVIDER: S-EPMC8242254 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Schistosoma japonicum eggs trapped in host liver secretes microRNA (miRNA)-containing extracellular vesicles (EVs) that can be transferred to host cells. Recent studies demonstrated that miRNAs derived from plants can modulate gene expression and phenotype of mammalian cells in a cross-kingdom manner. In this study, we identified a Schistosoma japonicum miRNA (e.g., Sja-miR-3096) that is present in the hepatocytes of mice infected with the parasite and has notable antitumor effects in both in vitro and in vivo models. The Sja-miR-3096 mimics suppressed cell proliferation and migration of both murine and human hepatoma cell lines by targeting phosphoinositide 3-kinase class II alpha (PIK3C2A). We generated a murine hepatoma cell line that stably expressed the pri-Sja-miR-3096 gene and demonstrated cross-species processing of the schistosome pri-miRNA to the mature Sja-miR-3096 in the mammalian cell. Importantly, inoculation of this cell line into the scapula and livers of mice led to a complete suppression of tumorigenesis of the hepatoma cells. Moreover, tumor weight was significantly reduced on intravenous administration of Sja-miR-3096 mimics. Thus, the schistosome miRNA-mediated antitumor activity occurs in host liver cells during schistosome infection, which may strengthen resistance of host to liver cancer, and discovery and development of such miRNAs may present promising interventions for cancer therapy.
| S-EPMC6831938 | biostudies-literature
Project description:Background:MicroRNA-125b (miR-125b) is downregulated in human cutaneous squamous cell carcinoma (CSCC). However, its function in CSCC has yet to be extensively explored. Here, we analyze the relationship between signal transducer and activator of transcription 3 (STAT3) and miR-125b in CSCC. Methods:Western blotting and quantitative RT-PCR were used to determine the expression of the miR-125b-STAT3 axis in human CSCC tissues and cell lines. The direct regulatory effect of miR-125b on STAT3 expression was assessed using a luciferase reporter gene assay and RNA immunoprecipitation assay. The MTT assay and flow cytometry were used to determine the role of the miR-125b-STAT3 axis in CSCC cell proliferation and apoptosis. Results:MiR-125b expression levels were significantly lower in CSCC cell lines and tissues than in normal cell lines and tissues. STAT3 was identified as the direct target of miR-125b. Upregulation of miR-125b and downregulation of STAT3 suppressed cell proliferation and promoted cell apoptosis. Cyclin D1 and Bcl2 were identified as the downstream targets of the miR-125-STAT3 axis. Conclusions:Our findings indicate that miR-125b acts as a tumor suppressor in CSCC by targeting the STAT3 pathway. This observation increases our understanding of the molecular mechanisms of CSCC. Therapies aimed at activating miR-125b or inhibiting STAT3 signaling should be explored as potential treatments for CSCC.
| S-EPMC7059386 | biostudies-literature
Project description:BackgroundSchistosomiasis japonica remains a significant public health problem in China and Southeast Asian countries. The most typical and serious outcome of the chronic oriental schistosomiasis is the progressive granuloma and fibrosis in the host liver, which has been a major medical challenge. However, the molecular mechanism underling the hepatic pathogenesis is still not clear.Methodology and principal findingsUsing microarrays, we quantified the temporal gene expression profiles in the liver of Schistosoma japonicum-infected BALB/c mice at 15, 30, and 45 day post infection (dpi) with that from uninfected mice as controls. Gene expression alternation associated with liver damage was observed in the initial phase of infection (dpi 15), which became more magnificent with the onset of egg-laying. Up-regulated genes were dominantly associated with inflammatory infiltration, whereas down-regulated genes primarily led to the hepatic functional disorders. Simultaneously, microRNA profiles from the same samples were decoded by Solexa sequencing. More than 130 miRNAs were differentially expressed in murine liver during S. japonicum infection. MiRNAs significantly dysregulated in the mid-phase of infection (dpi 30), such as mmu-miR-146b and mmu-miR-155, may relate to the regulation of hepatic inflammatory responses, whereas miRNAs exhibiting a peak expression in the late phase of infection (dpi 45), such as mmu-miR-223, mmu-miR-146a/b, mmu-miR-155, mmu-miR-34c, mmu-miR-199, and mmu-miR-134, may represent a molecular signature of the development of schistosomal hepatopathy. Further, a dynamic miRNA-gene co-expression network in the progression of infection was constructed.Conclusions and significanceThis study presents a global view of dynamic expression of both mRNA and miRNA transcripts in murine liver during S. japonicum infection, and highlights that miRNAs may play a variety of regulatory roles in balancing the immune responses during the development of hepatic pathology. The data provide robust information for further researches on the pathogenesis and molecular events of hepatopathy induced by schistosome eggs.
| S-EPMC3692539 | biostudies-literature
Project description:The present study was to determine the targeting effect of M13 phage peptide ZL4 (MppZL4) on Schistosoma japonicum (S.j). Mice infected with S.j were injected with MppZL4. Real-time PCR was used to detect the distribution and metabolism of MppZL4 in the livers and lungs of mice. In vivo refusion test was performed to detect the targeting of MppZL4. Western blotting was employed to determine the expression of MppZL4. Live imaging was used to detect the distribution of oligopeptide MppZL4. Immunohistochemistry was employed to determine MppZL4 location on adult S.j body surface. Gomori method was employed to detect the influence of oligopeptide MppZL4 on alkaline phosphatase activity. The distribution and metabolism of MppZL4 and M13KE are not significantly different from each other at each time point. The abundance of MppZL4 is changed as S.j migrates in mice. The targeted binding effect of MppZL4 varies at different stages. ZL4 oligopeptide targets S.j in mice. The specific binding sites of MppZL4 on S.j body are mainly located in syncytial cells. The binding sites of MppZL4 on S.j body surface might be ALP or ALP-related proteins. MppZL4 had targeted binding effect on S.j with its binding site being associated with proteins related to S.j alkaline phosphatase. S.j tegument had a specifically binding site with exogenous peptides, offering new means to explore the interactions between hosts and parasites. Additionally, MppZL4 can possibly be used as targeting molecules in worm-resistant drugs or as tracing molecules in imaging diagnosis technologies.
| S-EPMC4396255 | biostudies-literature
Project description:Schistosomiasis remains a serious parasitic disease, which is characterized by granulomatous inflammation and hepatic fibrosis. MicroRNAs derived from parasites can regulate host genes and cell phenotype. Here, we showed that a miRNA derived from S. japonicum (Sja-miR-1) exists in the hepatic stellate cells (HSCs) of mice infected with the parasite and up-regulates the expression of collagens and α-SMA by targeting secreted frizzled-related protein 1 (SFRP1). A vector-mediated delivery of Sja-miR-1 into naive mice led to hepatic fibrogenesis in the mice. Accordingly, inhibition of Sja-miR-1 in the infected mice led to reduction of the parasite-induced hepatic fibrosis. The mechanism behind the Sja-miR-1-mediated activation of HSC could be through targeting SFRP1 to regulate the Wnt/β-catenin pathway. These findings reveal that parasite-derived small non-coding RNAs are implicated in cross-species regulation of host pathological process and persistent inhibition of Sja-miR-1 may provide a therapeutic potential for the parasite diseases.
| S-EPMC7082693 | biostudies-literature
Project description:Eggs produced by bisexual infected mature female worms (MF) of Schistosoma japonicum are important in the transmission of the parasite and responsible for the pathogenesis of schistosomiasis. The single-sex infected female worms (SF) cannot mature and do not produce normal eggs; also they do not induce severe damage to the host. In this study, the microRNA (miRNA) expression profiles of 25d MF and 25d SF were investigated through Solexa deep-sequencing technology to explore the developmental mechanisms of schistosome female worms. There were 36 differentially expressed miRNA, 20 up-regulated and 16 down-regulated found in MF/SF worms, including some development related miRNA such as bantam (ban), let-7, miR-124, miR-8, miR-1, miR-7. There were 166 target genes of up-regulated miRNA and 201 target genes of down-regulated miRNA after comparing the target gene prediction software results with RNA-Seq transcriptome results. Analysis of the target genes shows that different ones are involved in MF and SF worms in Gene Ontology terms, with a similar situation in KEGG. This observation indicates that different genes regulated by differentially expressed miRNA take part in MF and SF and lead to differential sexual status. This means that the sexual status of female worms is regulated by miRNA.
| S-EPMC7519503 | biostudies-literature
Project description:CD146, an endothelial biomarker, has been shown to be aberrantly upregulated during pathological angiogenesis and functions as a coreceptor for vascular endothelial growth factor receptor 2 (VEGFR-2) to promote disease progression. However, the regulatory mechanisms of CD146 expression during angiogenesis remain unclear. Using a microRNA screening approach, we identified a novel negative regulator of angiogenesis, microRNA 329 (miR-329), that directly targeted CD146 and inhibited CD146-mediated angiogenesis in vitro and in vivo. Endogenous miR-329 expression was downregulated by VEGF and tumor necrosis factor alpha (TNF-?), resulting in the elevation of CD146 in endothelial cells. Upregulation of CD146 facilitated an endothelial response to VEGF-induced SRC kinase family (SKF)/p38 mitogen-activated protein kinase (MAPK)/NF-?B activation and consequently promoted endothelial cell migration and tube formation. Our animal experiments showed that treatment with miR-329 repressed excessive CD146 expression on blood vessels and significantly attenuated neovascularization in a mouse model of pathological angiogenesis. Our findings provide the first evidence that CD146 expression in angiogenesis is regulated by miR-329 and suggest that miR-329 could present a potential therapeutic tool for the treatment of angiogenic diseases.
| S-EPMC3753872 | biostudies-other
Project description:Praziquantel (PZQ), a traditional helminthicide drug, has been shown to exert an anti-inflammatory effect on splenomegaly induced by schistosomiasis via regulating macrophage polarization. Meanwhile, miR-21 has been demonstrated to control macrophage polarization. However, the role of miR-21 in the regulation of macrophage polarization by PZQ in schistosomiasis is still unclear. In the present study, we found that M1-type macrophages were the predominant splenic macrophages in chronic schistosomiasis and that NLRP3 inflammasome-related molecules were upregulated. PZQ inhibited NLRP3 inflammasome in M1 macrophages and reduced the expression of miR-21. Furthermore, using the methods of quantitative real-time PCR and transfection, the downregulation of NLRP3/IL-1β by PZQ in M1 macrophages were reversed by miR-21 overexpression. These results indicated that miR-21 was involved in the inhibiting effect of PZQ on activation of NLRP3 inflammasome. Moreover, miR-21 might target Smad7 to mediate the anti-inflammatory effect of PZQ in polarized macrophages. This study provides an in-depth mechanism of PZQ in the treatment of schistosomiasis.
| S-EPMC7029728 | biostudies-literature
Project description:Schistosomiasis japonica remains a significant public health problem in China and Southeast Asian countries. The most typical and serious outcome of the chronic oriental schistosomiasis is the progressive granuloma and fibrosis in the host liver, which has been a major medical challenge. However, the molecular mechanisms that underlie the hepatic pathogenesis induced by schistosomal egg deposition have not yet been well-defined. Using microarrays, we quantified the temporal gene expression profiles in the liver of Schistosoma japonicum-infected BALB/c mice at day 15, 30, and 45 post infection (pi) with that from uninfected mice as controls. Meanwhile, microRNA expression profiles from the same samples were decoded by parallel solexa sequencing. Gene expression alternation associated with liver damage was observed even at early stage of infection (e.g., pi 15), which became more magnificent onset of egg deposition within the liver tissue. Up-regulated genes were dominantly associated with inflammatory infiltration of liver during S. japonicum infection, whereas down-regulated genes primarily led to the hepatic functional disorders. More than 130 miRNAs were differentially expressed during S. japonicum infection, and dynamic miRNA-gene co-expression network has been constructed during the development of hepatic pathology.
2013-06-12 | GSE45985 | GEO
Project description:Acetylcholinesterase (AChE) is an important metabolic enzyme of schistosomes present in the musculature and on the surface of the blood stage where it has been implicated in the modulation of glucose scavenging from mammalian host blood. As both a target for the antischistosomal drug metrifonate and as a potential vaccine candidate, AChE has been characterised in the schistosome species Schistosoma mansoni, S. haematobium and S. bovis, but not in S. japonicum. Recently, using a schistosome protein microarray, a predicted S. japonicum acetylcholinesterase precursor was significantly targeted by protective IgG1 immune responses in S. haematobium-exposed individuals that had acquired drug-induced resistance to schistosomiasis after praziquantel treatment.We report the full-length cDNA sequence and describe phylogenetic and molecular structural analysis to facilitate understanding of the biological function of AChE (SjAChE) in S. japonicum. The protein has high sequence identity (88 %) with the AChEs in S. mansoni, S. haematobium and S. bovis and has 25 % sequence similarity with human AChE, suggestive of a highly specialised role for the enzyme in both parasite and host. We immunolocalized SjAChE and demonstrated its presence on the surface of adult worms and schistosomula, as well as its lower expression in parenchymal regions. The relatively abundance of AChE activity (90 %) present on the surface of adult S. japonicum when compared with that reported in other schistosomes suggests SjAChE may be a more effective drug or immunological target against this species. We also demonstrate that the classical inhibitor of AChE, BW285c51, inhibited AChE activity in tegumental extracts of paired worms, single males and single females by 59, 22 and 50 %, respectively, after 24 h incubation with 200 ?M BW284c51.These results build on previous studies in other schistosome species indicating major differences in the enzyme between parasite and mammalian host, and provide further support for the design of an anti-schistosome intervention targeting AChE.
| S-EPMC4901427 | biostudies-literature