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AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3

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Abstract

Epithelial-mesenchymal transition (EMT) in peritoneum was induced during peritoneal dialysis (PD), which finally caused progressive fibrosis. However, the underlying mechanisms were not well elucidated. We established advanced glycation end-products (AGEs)-induced EMT model using primary human peritoneal mesothelial cells (HPMCs). The working concentration and time of AGEs were optimized. Then the expression and activation signal transducer and activator of transcription 3 (STAT3), a key factor of EMT in cancer, were detected. The regulation of STAT3 by miRNA was also explored. 50 μg/ml AGEs treatment for 24 h can successfully induce EMT in HPMCs. AGEs treatment upregulated and activated STAT3. miRNA-454, potentially targeting STAT3, was down-regulated in AGEs-treated HPMCs. Overexpression of miRNA-454 prevented AGEs- induced EMT in HPMCs. AGEs induce epithelial to mesenchymal transformation of Human peritoneal mesothelial cells via upregulation of STAT3.

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References

  1. Krediet, R.T.: The peritoneal membrane in chronic peritoneal dialysis. Kidney Int. 55(1), 341–356 (1999). https://doi.org/10.1046/j.1523-1755.1999.00264.x

    Article  CAS  PubMed  Google Scholar 

  2. Strippoli, R., Moreno-Vicente, R., Battistelli, C., Cicchini, C., Noce, V., Amicone, L., Marchetti, A., Del Pozo, M.A., Tripodi, M.: Molecular mechanisms underlying peritoneal EMT and fibrosis. Stem Cells Int. 3543678, 2016, (2016). https://doi.org/10.1155/2016/3543678

  3. Aroeira, L.S., Aguilera, A., Sanchez-Tomero, J.A., Bajo, M.A., del Peso, G., Jimenez-Heffernan, J.A., Selgas, R., Lopez-Cabrera, M.: Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions. J. Am. Soc. Nephrol. 18(7), 2004–2013 (2007). https://doi.org/10.1681/ASN.2006111292

    Article  CAS  PubMed  Google Scholar 

  4. Yanez-Mo, M., Lara-Pezzi, E., Selgas, R., Ramirez-Huesca, M., Dominguez-Jimenez, C., Jimenez-Heffernan, J.A., Aguilera, A., Sanchez-Tomero, J.A., Bajo, M.A., Alvarez, V., Castro, M.A., del Peso, G., Cirujeda, A., Gamallo, C., Sanchez-Madrid, F., Lopez-Cabrera, M.: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N. Engl. J. Med. 348(5), 403–413 (2003). https://doi.org/10.1056/NEJMoa020809

    Article  PubMed  Google Scholar 

  5. Rosenberg, M.E.: Peritoneal dialysis: diabetes of the peritoneal cavity. J. Lab. Clin. Med. 134(2), 103–104 (1999)

    Article  CAS  PubMed  Google Scholar 

  6. Li, B., Huang, C.: Regulation of EMT by STAT3 in gastrointestinal cancer (review). Int. J. Oncol. 50(3), 753–767 (2017). https://doi.org/10.3892/ijo.2017.3846

    Article  CAS  PubMed  Google Scholar 

  7. Stylianou, E., Jenner, L.A., Davies, M., Coles, G.A., Williams, J.D.: Isolation, culture and characterization of human peritoneal mesothelial cells. Kidney Int. 37(6), 1563–1570 (1990)

    Article  CAS  PubMed  Google Scholar 

  8. Zhang, X., Yue, P., Page, B.D., Li, T., Zhao, W., Namanja, A.T., Paladino, D., Zhao, J., Chen, Y., Gunning, P.T., Turkson, J.: Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc. Natl. Acad. Sci. U. S. A. 109(24), 9623–9628 (2012). https://doi.org/10.1073/pnas.1121606109

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zeisberg, M., Neilson, E.G.: Biomarkers for epithelial-mesenchymal transitions. J. Clin. Invest. 119(6), 1429–1437 (2009). https://doi.org/10.1172/JCI36183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lamouille, S., Xu, J., Derynck, R.: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15(3), 178–196 (2014). https://doi.org/10.1038/nrm3758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang, Q., Yang, X., Xu, Y., Shen, Z., Cheng, H., Cheng, F., Liu, X., Wang, R.: RhoA/rho-kinase triggers epithelial-mesenchymal transition in mesothelial cells and contributes to the pathogenesis of dialysis-related peritoneal fibrosis. Oncotarget. 9(18), 14397–14412 (2018). https://doi.org/10.18632/oncotarget.24208

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chen, H., Liu, W., Wu, X., Gou, M., Shen, J., Wang, H.: Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways. Int. Immunopharmacol. 52, 143–149 (2017). https://doi.org/10.1016/j.intimp.2017.09.004

    Article  CAS  PubMed  Google Scholar 

  13. Huang, C.Y., Lai, K.Y., Hung, L.F., Wu, W.L., Liu, F.C., Ho, L.J.: Advanced glycation end products cause collagen II reduction by activating Janus kinase/signal transducer and activator of transcription 3 pathway in porcine chondrocytes. Rheumatology (Oxford). 50(8), 1379–1389 (2011). https://doi.org/10.1093/rheumatology/ker134

    Article  CAS  Google Scholar 

  14. Liu, J., Zhong, Y., Liu, G., Zhang, X., Xiao, B., Huang, S., Liu, H., He, L.: Role of Stat3 signaling in control of EMT of tubular epithelial cells during renal fibrosis. Cell. Physiol. Biochem. 42(6), 2552–2558 (2017). https://doi.org/10.1159/000480216

    Article  CAS  PubMed  Google Scholar 

  15. Wendt, M.K., Balanis, N., Carlin, C.R., Schiemann, W.P.: STAT3 and epithelial-mesenchymal transitions in carcinomas. JAKSTAT. 3(1), e28975 (2014). https://doi.org/10.4161/jkst.28975

    Article  PubMed  PubMed Central  Google Scholar 

  16. Haghikia, A., Hoch, M., Stapel, B., Hilfiker-Kleiner, D.: STAT3 regulation of and by microRNAs in development and disease. JAKSTAT. 1(3), 143–150 (2012). https://doi.org/10.4161/jkst.19573

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhong, Z., Wen, Z., Darnell Jr., J.E.: Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 264(5155), 95–98 (1994)

    Article  CAS  PubMed  Google Scholar 

  18. Guo, Y., Xu, F., Lu, T., Duan, Z., Zhang, Z.: Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat. Rev. 38(7), 904–910 (2012). https://doi.org/10.1016/j.ctrv.2012.04.007

    Article  CAS  PubMed  Google Scholar 

  19. Sullivan, N.J., Sasser, A.K., Axel, A.E., Vesuna, F., Raman, V., Ramirez, N., Oberyszyn, T.M., Hall, B.M.: Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 28(33), 2940–2947 (2009). https://doi.org/10.1038/onc.2009.180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xu, J., Lamouille, S., Derynck, R.: TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19(2), 156–172 (2009). https://doi.org/10.1038/cr.2009.5

    Article  CAS  PubMed  Google Scholar 

  21. Xu, M.Y., Hu, J.J., Shen, J., Wang, M.L., Zhang, Q.Q., Qu, Y., Lu, L.G.: Stat3 signaling activation crosslinking of TGF-beta1 in hepatic stellate cell exacerbates liver injury and fibrosis. Biochim. Biophys. Acta. 1842(11), 2237–2245 (2014). https://doi.org/10.1016/j.bbadis.2014.07.025

    Article  CAS  PubMed  Google Scholar 

  22. Grabenstatter, H.L., Del Angel, Y.C., Carlsen, J., Wempe, M.F., White, A.M., Cogswell, M., Russek, S.J., Brooks-Kayal, A.R.: The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol. Dis. 62, 73–85 (2014). https://doi.org/10.1016/j.nbd.2013.09.003

    Article  CAS  PubMed  Google Scholar 

  23. Yokota, T., Omachi, K., Suico, M.A., Kamura, M., Kojima, H., Fukuda, R., Motomura, K., Teramoto, K., Kaseda, S., Kuwazuru, J., Takeo, T., Nakagata, N., Shuto, T., Kai, H.: STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model. Nephrol. Dial. Transplant. 33(2), 214–223 (2018). https://doi.org/10.1093/ndt/gfx246

    Article  CAS  PubMed  Google Scholar 

  24. Shukla, G.C., Singh, J., Barik, S.: MicroRNAs: processing, maturation. Target Recognition and Regulatory Functions. Mol Cell Pharmacol. 3(3), 83–92 (2011)

    CAS  PubMed  Google Scholar 

  25. Zhang, L., Li, J., Wang, Q., Meng, G., Lv, X., Zhou, H., Li, W., Zhang, J.: The relationship between microRNAs and the STAT3-related signaling pathway in cancer. Tumour Biol. 39(7), 1010428317719869 (2017). https://doi.org/10.1177/1010428317719869

    Article  PubMed  Google Scholar 

  26. Li, X., Yu, Z., Li, Y., Liu, S., Gao, C., Hou, X., Yao, R., Cui, L.: The tumor suppressor miR-124 inhibits cell proliferation by targeting STAT3 and functions as a prognostic marker for postoperative NSCLC patients. Int. J. Oncol. 46(2), 798–808 (2015). https://doi.org/10.3892/ijo.2014.2786

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, J., Lu, Y., Yue, X., Li, H., Luo, X., Wang, Y., Wang, K., Wan, J.: MiR-124 suppresses growth of human colorectal cancer by inhibiting STAT3. PLoS One. 8(8), e70300 (2013). https://doi.org/10.1371/journal.pone.0070300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful for the support by the Nature Science Foundation of Anhui Province (1808085MH249).

Contributors

Pei Zhang designed the study. Hong Dai and Lei Peng were responsible for the acquisition of data. Pei Zhang was the major contributors in drafting and revising the manuscript. Pei Zhang was final approval of the version to be submitted. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, No 218, Jixi Road, Hefei, 230022, Anhui, China

    Pei Zhang & Hong Dai

  2. Institute of pharmacology, AnHui Medical University, AnHui, Hefei, 230032, China

    Lei Peng

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  1. Pei Zhang
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  2. Hong Dai
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Correspondence to Pei Zhang.

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HPMCs were isolated from freshly obtained omental fat following the method described by Stylianou et al. with minor modification. This study was approved by the First Affiliated Hospital of Anhui Medical University.

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Zhang, P., Dai, H. & Peng, L. AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3. Glycoconj J 36, 155–163 (2019). https://doi.org/10.1007/s10719-019-09861-7

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