Dataset Information

Schistosoma mansoni eggs induce Wnt/?-catenin signaling and activate the protooncogene c-Jun in human and hamster colon.

ABSTRACT: Schistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/?-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and ?H2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.

SUBMITTER: Weglage J

PROVIDER: S-EPMC7758332 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Schistosoma mansoni eggs induce Wnt/β-catenin signaling and activate the protooncogene c-Jun in human and hamster colon.

Weglage Jakob J Wolters Friederike F Hehr Laura L Lichtenberger Jakob J Wulz Celina C Hempel Felix F Baier Anne A Quack Thomas T Köhler Kernt K Longerich Thomas T Schramm Gabriele G Irungbam Karuna K Mueller Heike H von Buelow Verena V Tschuschner Annette A Odenthal Margarete M Drebber Uta U Arousy Maha El ME Ramalho Leandra N Z LNZ Bankov Katrin K Wild Peter P Pons-Kühnemann Jörn J Tschammer Jonas J Grevelding Christoph G CG Roeb Elke E Roderfeld Martin M

Scientific reports 20201223 1

Schistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate th ...[more]

PMID: 33361772

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Project description:Clinical data have provided evidence that schistosomiasis can promote hepatocellular carcinogenesis. c-Jun and STAT3 are critical regulators of liver cancer development and progression. The aim of the present study was to investigate the hepatocellular activation of c-Jun and STAT3 by Schistosoma mansoni infection. Expression and function of c-Jun and STAT3 as well as proliferation and DNA repair were analyzed by western blotting, electrophoretic mobility-shift assay, and immunohistochemistry in liver of S. mansoni-infected hamsters, Huh7 cells, primary hepatocytes, and human liver biopsies. Hepatocellular activation of c-Jun was demonstrated by nuclear translocation of c-Jun, enhanced phosphorylation (Ser73), and AP-1/DNA-binding in response to S. mansoni infection. Nuclear c-Jun staining pattern around lodged eggs without ambient immune reaction, and directionally from granuloma to the central veins, suggested that substances released from schistosome eggs were responsible for the observed effects. In addition, hepatocytes with c-Jun activation show cell activation and DNA double-strand breaks. These findings from the hamster model were confirmed by analyses of human biopsies from patients with schistosomiasis. Cell culture experiments finally demonstrated that activation of c-Jun and STAT3 as well as DNA repair were induced by an extract from schistosome eggs (soluble egg antigens) and culture supernatants of live schistosome egg (egg-conditioned medium), and in particular by IPSE/alpha-1, the major component secreted by live schistosome eggs. The permanent activation of hepatocellular carcinoma-associated proto-oncogenes such as c-Jun and associated transcription factors including STAT3 by substances released from tissue-trapped schistosome eggs may be important factors contributing to the development of liver cancer in S. mansoni-infected patients. Therefore, identification and therapeutic targeting of the underlying pathways is a useful strategy to prevent schistosomiasis-associated carcinogenesis.

Project description:Background & aimsSchistosomiasis is a parasitic infection which affects more than 200 million people globally. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma.MethodsMetabolic reprogramming was analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging, liquid chromatography with high-resolution mass spectrometry, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies.ResultsThe infection with S. mansoni provokes hepatic exhaustion of neutral lipids and glycogen. Furthermore, the distribution of distinct lipid species and the regulation of rate-limiting metabolic enzymes is disrupted in the liver of S. mansoni infected animals. Notably, eggs mobilize, incorporate, and store host lipids, while the associated metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of reactive oxygen species scavengers ameliorates these deleterious effects.ConclusionsOur findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism via soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma.Impact and implicationsThe authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming, causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host's immune response. S. mansoni eggs take advantage of the host environment through metabolic reprogramming of hepatocytes and enterocytes. By inducing DNA damage, this neglected tropical disease might promote hepatocellular damage and thus influence international health efforts.

Project description:Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts. The infective schistosome cercaria develops from an undifferentiated germ ball within the daughter sporocyst in the molluscan host, during which considerable morphological development and synthesis of proteins essential for infection occurs. The free-living, non-feeding cercaria is notable for its swimming and host location behaviour. On contact with host skin it rapidly penetrates, replaces its tegument surface membranes, and begins body remodelling, before crossing the dermis to exit the skin via a blood vessel. Such a ‘violent’ transition from snail to fresh water to mammalian host should be accompanied by remarkable changes in the patterns of gene expression. All gene models from version E of the S. mansoni genome (www.GeneDB.org) were incorporated into a 350K feature Roche-NimbleGen, high-density oligonucleotide array. From a map-ordered list, every 13th 50mer was chosen as a probe. Double-stranded cDNA from three biological replicates each of germ balls, cercariae, and day 3 schistosomula was hybridised to the array without amplification. Statistical analysis was carried out using programmes from the Bioconductor suite (Gentleman et al. 2004 Genome Biol 5(10):R80). More than 1000 loci were shown to be differentially expressed in each of the comparisons between the three life cycle stages. Gene ontology (GO) analysis was then carried out to discover the categories enriched in each stage. In addition custom categories based on biological function (e.g. stress response) or parasite tissue (e.g. tegument) were analysed. Three biological replicates each of germ balls, cercariae, day 3 in vitro cultured schistosomula, and eggs were used. No technical replicates were included. This is the first genome-wide microarray platform for S. mansoni. It was used to investigate the gene expression patterns of the above lifecycle stages. The first three are the stages before, during and after penetration of mammalian host skin.

Dataset Information

Schistosoma mansoni eggs induce Wnt/?-catenin signaling and activate the protooncogene c-Jun in human and hamster colon.

Publications

Schistosoma mansoni eggs induce Wnt/β-catenin signaling and activate the protooncogene c-Jun in human and hamster colon.

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