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, 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 (SEA) and culture supernatants of live schistosome egg (egg-conditioned medium (ECM)), 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. This article is protected by copyright. All rights reserved.

Schistosomiasis is one of the most prominent parasite-induced infectious diseases, causing tremendous medical and socioeconomic problems. Current studies have reported on the spread of endemic regions and the fear of development of resistance against praziquantel, the only effective drug available. Among the Schistosoma species, only S. haematobium is classified as a Group 1 carcinogen (definitely cancerogenic to humans), causing squamous cell carcinoma of the bladder, whereas infection with S. mansoni is included in Group 3 of carcinogenic hazards to humans by the International Agency for Research on Cancer (IARC), indicating insufficient evidence to determine its carcinogenicity. Nevertheless, although S. mansoni has not been discussed as an organic carcinogen, the multiplicity of case reports, together with recent data from animal models and cell culture experiments, suggests that this parasite can predispose patients to or promote hepatic and colorectal cancer. In this review, we discuss the current data, with a focus on new developments regarding the association of S. mansoni infection with human cancer and the recently discovered biomolecular mechanisms by which S. mansoni may predispose patients to cancer development and carcinogenesis.

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/β-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.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.

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