Differential responses of epithelial cells from urinary and biliary tract to eggs of Schistosoma haematobium and S. mansoni

Rafael Nacif-Pimenta, Alessandra da Silva Orfanó, Ilana A Mosley, Shannon E Karinshak, Kenji Ishida, Victoria H Mann, Paulo Marcos Zech Coelho, José M Correia da Costa, Michael H Hsieh, Paul J Brindley, Gabriel Rinaldi, Rafael Nacif-Pimenta, Alessandra da Silva Orfanó, Ilana A Mosley, Shannon E Karinshak, Kenji Ishida, Victoria H Mann, Paulo Marcos Zech Coelho, José M Correia da Costa, Michael H Hsieh, Paul J Brindley, Gabriel Rinaldi

Abstract

Chronic urogenital schistosomiasis can lead to squamous cell carcinoma of the bladder. The International Agency for Research on Cancer classifies the infection with S. haematobium as a group 1 carcinogen, a definitive cause of cancer. By contrast, hepatointestinal schistosomiasis due to the chronic infection with S. mansoni or S. japonicum associated with liver periportal fibrosis, does not apparently lead to malignancy. The effects of culturing human epithelial cells, HCV29, established from normal urothelium, and H69, established from cholangiocytes, in the presence of S. haematobium or S. mansoni eggs were investigated. Cell growth of cells co-cultured with schistosome eggs was monitored in real time, and gene expression analysis of oncogenesis, epithelial to mesenchymal transition and apoptosis pathways was undertaken. Schistosome eggs promoted proliferation of the urothelial cells but inhibited growth of cholangiocytes. In addition, the tumor suppressor P53 pathway was significantly downregulated when exposed to schistosome eggs, and downregulation of estrogen receptor was predicted in urothelial cells exposed only to S. haematobium eggs. Overall, cell proliferative responses were influenced by both the tissue origin of the epithelial cells and the schistosome species.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Proliferation of urothelial cells and cholangiocytes in response to schistosome eggs, monitored in real time using the xCELLigence system. Non-contact co-culture of Schistosoma mansoni and S. haematobium eggs with HCV29 cells (Panel A) or H69 cells (Panel B) over time after the addition of the eggs. Cell growth is expressed as percentage of the Normalized Cell Index of cells co-cultured with eggs compared with control cells (control cell growth rate = 100%). All curves represent the averages of at least three technical replicates for the experiment and standard deviations are shown as error bars at each data point. Blue and red asterisks indicate levels of significance (P ≤ 0.01) of growth ratios of cells cultured with S. mansoni and S. haematobium eggs, compared to control cells cultured in the absence of eggs, respectively. Sm live: S. mansoni live eggs; Sm heat-killed: heat-killed S. mansoni eggs; Sh live: S. haematobium live eggs; Sh heat-killed: heat-killed S. haematobium eggs.
Figure 2
Figure 2
Schistosome eggs induced dysregulation of oncogenes, tumor suppressors and EMT-related genes in HCV29 cells over time. Volcano plots of HCV29 cell gene response to non-contact co-culture with S. mansoni or S. haematobium eggs as indicated, for 2 (Panel A) or 24 (Panel B) hours. Gene expression was measured using qPCR gene arrays designed to assess oncogenesis- and EMT- associated transcripts. Significantly dysregulated (P < 0.05) genes with >±1.5-fold-change, are shown. Panel C. Venn diagram compiled only with the HCV29 cell culture conditions that share differentially expressed genes (DEG) – only upregulated genes were shared among the 3 indicated conditions. (Table S2 includes the complete set of DEG indicated in the Venn diagram).
Figure 3
Figure 3
Schistosome eggs induced dysregulation of apoptosis-related genes in H69 cells. Volcano plot of the H69 cell gene response to non-contact co-culture with S. mansoni or S. haematobium eggs as indicated for 24 hours. Gene expression was measured using qPCR gene arrays designed to assess apoptosis-associated transcripts. Significantly dysregulated (P < 0.05) genes with >±1.5-fold-change, are shown. (Table S1 includes the complete data set of gene expression changes.) Panel B. Venn diagram compiled only with the H69 cell culture conditions that share differentially expressed genes (DEG) – only downregulated genes were shared between the two conditions indicated.
Figure 4
Figure 4
Significant dysregulation of genes involved in Colorectal Cancer Signaling Pathway in urothelial cells. The pathway was significantly dysregulated at early time point in S. mansoni eggs co-cultured HCV29 cells, and all the perturbed genes were upregulated (genes colored in red). Adapted from map05210 Colorectal cancer, KEEG Database–.
Figure 5
Figure 5
Significant dysregulation of P53 pathway in urothelial cells exposed to either S. haematobium or S. mansoni eggs for 24 hours. P53 pathway highlighting upregulated or downregulated genes in red or green, respectively. Genes affected by S. mansoni or S. haematobium are indicated by blue or red squares, respectively. Adapted from map04115 p53 signaling pathway, KEEG Database–.
Figure 6
Figure 6
Upstream regulatory analysis (URA) of differentially expressed genes (DEGs) predicted the estrogen receptor and beta-estradiol (P < 0.05) to be inhibited in HCV29 cells co-culture for 24 h with S. haematobium eggs. Panel A. Significantly upregulated genes are shown in red. These genes, negatively regulated (T-symbol) by the estrogen receptor, were found to be upregulated in HCV29 cells co-cultured with S. haematobium eggs for 24 hours; red dashed lines indicate that these genes were activated. Therefore, the URA analysis significantly predicted the estrogen receptor as an inhibited upstream regulator of this set of genes in this dataset. Panel B. Significantly downregulated genes are shown in green. These genes, positively regulated (arrow) by beta-estradiol, were found to be downregulated in HCV29 cells co-cultured with S. haematobium eggs for 24 hours; blue dashed lines indicate that these genes were inhibited in our dataset. Therefore, the URA analysis significantly predicted beta-estradiol as an inhibited upstream regulator of this set of genes in the dataset.

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