IPSE, an abundant egg-secreted protein of the carcinogenic helminth Schistosoma haematobium , promotes proliferation of
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(2020) 15:63
RESEARCH ARTICLE
Open Access
IPSE, an abundant egg-secreted protein of the carcinogenic helminth Schistosoma haematobium, promotes proliferation of bladder cancer cells and angiogenesis Evaristus C. Mbanefo1, Chinwike Terry Agbo2, Yuanlong Zhao3, Olivia K. Lamanna1, Kim H. Thai4, Shannon E. Karinshak5, Mohammad Afzal Khan6, Chi-Ling Fu7, Justin I. Odegaard8, Irina V. Saltikova8,9, Michael J. Smout10, Luke F. Pennington11, Mark R. Nicolls12, Theodore S. Jardetzky11, Alex Loukas10, Paul J. Brindley5, Franco H. Falcone13 and Michael H. Hsieh1*
Abstract Background: Schistosoma haematobium, the helminth causing urogenital schistosomiasis, is a known bladder carcinogen. Despite the causal link between S. haematobium and bladder cancer, the underlying mechanisms are poorly understood. S. haematobium oviposition in the bladder is associated with angiogenesis and urothelial hyperplasia. These changes may be pre-carcinogenic events in the bladder. We hypothesized that the Interleukin-4inducing principle of Schistosoma mansoni eggs (IPSE), an S. haematobium egg-secreted “infiltrin” protein that enters host cell nuclei to alter cellular activity, is sufficient to induce angiogenesis and urothelial hyperplasia. Methods: Mouse bladders injected with S. haematobium eggs were analyzed via microscopy for angiogenesis and urothelial hyperplasia. Endothelial and urothelial cell lines were incubated with recombinant IPSE protein or an IPSE mutant protein that lacks the native nuclear localization sequence (NLS-) and proliferation measured using CFSE staining and real-time monitoring of cell growth. IPSE’s effects on urothelial cell cycle status was assayed through propidium iodide staining. Endothelial and urothelial cell uptake of fluorophore-labeled IPSE was measured. Findings: Injection of S. haematobium eggs into the bladder triggers angiogenesis, enhances leakiness of bladder blood vessels, and drives urothelial hyperplasia. Wild type IPSE, but not NLS-, increases proliferation of endothelial and urothelial cells and skews urothelial cells towards S phase. Finally, IPSE is internalized by both endothelial and urothelial cells. Interpretation: IPSE drives endothelial and urothelial proliferation, which may depend on internalization of the molecule. The urothelial effects of IPSE depend upon its NLS. Thus, IPSE is a candidate procarcinogenic molecule of S. haematobium. (Continued on next page)
* Correspondence: [email protected] 1 Division of Urology, Department of Surgery, Children’s National Hospital, West Wing, 4th Floor, 111 Michigan Avenue NW, Washington, DC 20010, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were mad
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