Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Increased α2-6 sialylation of endometrial cells contributes to the development of endometriosis

  • Choi, Hee-Jin (Department of Korean Medical Science, School of Korean Medicine) ;
  • Chung, Tae-Wook (Healthy Aging Korean Medical Research Center, Pusan National University) ;
  • Choi, Hee-Jung (Healthy Aging Korean Medical Research Center, Pusan National University) ;
  • Han, Jung Ho (Department of Korean Medical Science, School of Korean Medicine) ;
  • Choi, Jung-Hye (Department of Life and Nanopharmaceutical Sciences and Department of Oriental Pharmacy, Kyung Hee University) ;
  • Kim, Cheorl-Ho (Department of Biological Science, Sungkyunkwan University) ;
  • Ha, Ki-Tae (Department of Korean Medical Science, School of Korean Medicine)
  • Received : 2017.11.07
  • Accepted : 2018.06.12
  • Published : 2018.12.30
⟨ Previous Next ⟩

Abstract

Endometriosis is a disease characterized by implants of endometrial tissue outside the uterine cavity and is strongly associated with infertility. Focal adhesion of endometrial tissue to the peritoneum is an indication of incipient endometriosis. In this study, we examined the effect of various cytokines that are known to be involved in the pathology of endometriosis on endometrial cell adhesion. Among the investigated cytokines, transforming growth factor-${\beta}1$ ($TGF-{\beta}1$) increased adhesion of endometrial cells to the mesothelium through induction of ${\alpha}2-6$ sialylation. The expression levels of ${\beta}$-galactoside ${\alpha}2-6$ sialyltransferase (ST6Gal) 1 and ST6Gal2 were increased through activation of $TGF-{\beta}RI/SMAD2/3$ signaling in endometrial cells. In addition, we discovered that terminal sialic acid glycan epitopes of endometrial cells engage with sialic acid-binding immunoglobulin-like lectin-9 expressed on mesothelial cell surfaces. Interestingly, in an in vivo mouse endometriosis model, inhibition of endogenous sialic acid binding by a $NeuAc{\alpha}2-6Gal{\beta}1$-4GlcNAc injection diminished $TGF-{\beta}1$-induced formation of endometriosis lesions. Based on these results, we suggest that increased sialylation of endometrial cells by $TGF-{\beta}1$ promotes the attachment of endometrium to the peritoneum, encouraging endometriosis outbreaks.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. Bulun, S. E. Endometriosis. N. Engl. J. Med. 360, 268-279 (2009). https://doi.org/10.1056/NEJMra0804690
  2. Giudice, L. C. & Kao, L. C. Endometriosis. Lancet 364, 1789-1799 (2004). https://doi.org/10.1016/S0140-6736(04)17403-5
  3. Young, V. J., Brown, J. K., Saunders, P. T. & Horne, A. W. The role of the peritoneum in the pathogenesis of endometriosis. Hum. Reprod. Update 19, 558-569 (2013). https://doi.org/10.1093/humupd/dmt024
  4. Miller, J. E. et al. Implications of immune dysfunction on endometriosis associated infertility. Oncotarget 8, 7138-7147 (2017).
  5. Sundqvist, J., Andersson, K. L., Scarselli, G., Gemzell-Danielsson, K. & Lalitkumar, P. G. Expression of adhesion, attachment and invasion markers in eutopic and ectopic endometrium: a link to the aetiology of endometriosis. Hum. Reprod. 27, 2737-2746 (2012). https://doi.org/10.1093/humrep/des220
  6. Burney, R. O. & Giudice, L. C. Pathogenesis and pathophysiology of endometriosis. Fertil. Steril. 98, 511-519 (2012). https://doi.org/10.1016/j.fertnstert.2012.06.029
  7. Barcz, E. et al. Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration. Fertil. Steril. 97, 1380-1386 (2012). https://doi.org/10.1016/j.fertnstert.2012.03.057
  8. Omwandho, C. O., Konrad, L., Halis, G., Oehmke, F. & Tinneberg, H. R. Role of Tgf-betas in normal human endometrium and endometriosis. Hum. Reprod. 25, 101-109 (2010). https://doi.org/10.1093/humrep/dep382
  9. Wu, M. Y. & Ho, H. N. The role of cytokines in endometriosis. Am. J. Reprod. Immunol. 49, 285-296 (2003). https://doi.org/10.1034/j.1600-0897.2003.01207.x
  10. Dall'Olio, F., Malagolini, N., Trinchera, M. & Chiricolo, M. Mechanisms of cancerassociated glycosylation changes. Front. Biosci. (Landmark Ed.) 17, 670-699 (2012). https://doi.org/10.2741/3951
  11. Lannoo, N. & Van Damme, E. J. Review/N-glycans: the making of a varied toolbox. Plant Sci. 239, 67-83 (2015). https://doi.org/10.1016/j.plantsci.2015.06.023
  12. Bassaganas, S. et al. Pancreatic cancer cell glycosylation regulates cell adhesion and invasion through the modulation of Alpha2beta1integrin and E-cadherin function. PLoS ONE 9, e98595 (2014). https://doi.org/10.1371/journal.pone.0098595
  13. Oliveira-Ferrer, L., Legler, K. & Milde-Langosch, K. Role of protein glycosylation in cancer metastasis. Semin. Cancer Biol. 44, 141-152 (2017). https://doi.org/10.1016/j.semcancer.2017.03.002
  14. Berkes, E., Muzinic, A., Rigo, J. Jr., Tinneberg, H. R. & Oehmke, F. The analysis of the human plasma N-glycome in endometriosis patients. Eur. J. Obstet. Gynecol. Reprod. Biol. 171, 107-115 (2013). https://doi.org/10.1016/j.ejogrb.2013.08.008
  15. Kocbek, V., Hevir-Kene, N., Bersinger, N. A., Mueller, M. D. & Rizner, T. L. Increased levels of biglycan in endometriomas and peritoneal fluid samples from ovarian endometriosis patients. Gynecol. Endocrinol. 30, 520-524 (2014). https://doi.org/10.3109/09513590.2014.898055
  16. Nakagawa, N. et al. Reactivity of Ca19-9 and Ca125 in histological subtypes of epithelial ovarian tumors and ovarian endometriosis. Acta Med. Okayama 69, 227-235 (2015).
  17. Rodgers, A. K., Nair, A., Binkley, P. A., Tekmal, R. & Schenken, R. S. Inhibition of Cd44 N- and O-linked glycosylation decreases endometrial cell lines attachment to peritoneal mesothelial cells. Fertil. Steril. 95, 823-825 (2011). https://doi.org/10.1016/j.fertnstert.2010.09.005
  18. Zeitvogel, A., Baumann, R. & Starzinski-Powitz, A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. Am. J. Pathol. 159, 1839-1852 (2001). https://doi.org/10.1016/S0002-9440(10)63030-1
  19. Nishida, M., Kasahara, K., Kaneko, M., Iwasaki, H. & Hayashi, K. Establishment of anew human endometrial adenocarcinoma cell line, Ishikawa cells, containing estrogen and progesterone receptors. Nihon Sanka Fujinka Gakkai Zasshi 37, 1103-1111 (1985).
  20. Somigliana, E. et al. Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum. Reprod. 14, 2944-2950 (1999). https://doi.org/10.1093/humrep/14.12.2944
  21. Yuan, Y., Wu, L., Shen, S., Wu, S. & Burdick, M. M. Effect of alpha 2,6 sialylation on integrin-mediated adhesion of breast cancer cells to fibronectin and collagen Iv. Life. Sci. 149, 138-145 (2016). https://doi.org/10.1016/j.lfs.2016.02.071
  22. Bull, C., Stoel, M. A., den Brok, M. H. & Adema, G. J. Sialic acids sweeten a tumor’s life. Cancer Res. 74, 3199-3204 (2014). https://doi.org/10.1158/0008-5472.CAN-14-0728
  23. Rodriguez-Garcia, A. et al. Tgf-Beta1 targets Smad, P38 Mapk, and Pi3k/Akt signaling pathways to induce Pfkfb3 gene expression and glycolysis in glioblastoma cells. Febs. J. 284, 3437-3454 (2017). https://doi.org/10.1111/febs.14201
  24. O'Reilly, M. K. & Paulson, J. C. Siglecs as targets for therapy in immune-cellmediated disease. Trends Pharmacol. Sci. 30, 240-248 (2009). https://doi.org/10.1016/j.tips.2009.02.005
  25. Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nat. Rev. Immunol. 7, 255-266 (2007). https://doi.org/10.1038/nri2056
  26. Pinho, S. S. & Reis, C. A. Glycosylation in cancer: mechanisms and clinical implications. Nat. Rev. Cancer 15, 540-555 (2015). https://doi.org/10.1038/nrc3982
  27. Ohtsubo, K. & Marth, J. D. Glycosylation in cellular mechanisms of health and disease. Cell 126, 855-867 (2006). https://doi.org/10.1016/j.cell.2006.08.019
  28. Axford, J. The impact of glycobiology on medicine. Trends Immunol. 22, 237-239 (2001). https://doi.org/10.1016/S1471-4906(01)01890-7
  29. Cui, H., Lin, Y., Yue, L., Zhao, X. & Liu, J. Differential expression of the alpha2,3- sialic acid residues in breast cancer is associated with metastatic potential. Oncol. Rep. 25, 1365-1371 (2011).
  30. Lin, S., Kemmner, W., Grigull, S. & Schlag, P. M. Cell surface alpha 2,6 sialylation affects adhesion of breast carcinoma cells. Exp. Cell Res. 276, 101-110 (2002). https://doi.org/10.1006/excr.2002.5521
  31. Jones, C. J., Denton, J. & Fazleabas, A. T. Morphological and glycosylation changes associated with the endometrium and ectopic lesions in a baboon model of endometriosis. Hum. Reprod. 21, 3068-3080 (2006). https://doi.org/10.1093/humrep/del310
  32. Jones, C. J., Inuwa, I. M., Nardo, L. G., Litta, P. & Fazleabas, A. T. Eutopic endometrium from women with endometriosis shows altered ultrastructure and glycosylation compared to that from healthy controls-a pilot observational study. Reprod. Sci. 16, 559-572 (2009). https://doi.org/10.1177/1933719109332825
  33. Witz, C. A. Pathogenesis of endometriosis. Gynecol. Obstet. Invest. 53, 52-62 (2002). https://doi.org/10.1159/000049425
  34. Massague, J. TGF beta in cancer. Cell 134, 215-230 (2008). https://doi.org/10.1016/j.cell.2008.07.001
  35. Pizzo, A. et al. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol. Obstet. Invest. 54, 82-87 (2002). https://doi.org/10.1159/000067717
  36. Young, V. J., Brown, J. K., Saunders, P. T., Duncan, W. C. & Horne, A. W. The peritoneum is both a source and target of Tgf-Beta in women with endometriosis. PLoS ONE 9, e106773 (2014). https://doi.org/10.1371/journal.pone.0106773
  37. D'Hooghe, T. M., Xiao, L. & Hill, J. A. Cytokine profiles in autologous peritoneal fluid and peripheral blood of women with deep and superficial endometriosis. Arch. Gynecol. Obstet. 265, 40-44 (2001). https://doi.org/10.1007/s004040000126
  38. Harduin-Lepers, A. et al. Sialyltransferases functions in cancers. Front Biosci. (Elite Ed.) 4, 499-515 (2012).
  39. Lehoux, S. et al. Transcriptional regulation of the human St6gal2 gene in cerebral cortex and neuronal cells. Glycoconj. J. 27, 99-114 (2010). https://doi.org/10.1007/s10719-009-9260-y
  40. Krzewinski-Recchi, M. A. et al. Identification and functional expression of a second human beta-galactoside alpha2,6-sialyltransferase, St6gal Ii. Eur. J. Biochem. 270, 950-961 (2003). https://doi.org/10.1046/j.1432-1033.2003.03458.x
  41. Hsieh, C. C. et al. Elevation of beta-galactoside alpha2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis. Oncotarget 8, 7691-7709 (2017).
  42. Takashima, S., Tsuji, S. & Tsujimoto, M. Characterization of the second type of human beta-galactoside alpha 2,6-sialyltransferase (St6gal Ii), which sialylates galbeta 1,4glcnac structures on oligosaccharides preferentially. genomic analysis of human sialyltransferase genes. J. Biol. Chem. 277, 45719-45728 (2002). https://doi.org/10.1074/jbc.M206808200
  43. Aas-Eng, D. A., Asheim, H. C., Deggerdal, A., Smeland, E. & Funderud, S. Characterization of a promoter region supporting transcription of a novel human beta-galactoside alpha-2,6-sialyltransferase transcript in Hepg2 cells. Biochim. Biophys. Acta 1261, 166-169 (1995). https://doi.org/10.1016/0167-4781(94)00250-7
  44. Lu, J. et al. Beta-galactoside alpha2,6-sialyltranferase 1 promotes transforming growth factor-beta-mediated epithelial-mesenchymal transition. J. Biol. Chem. 289, 34627-34641 (2014). https://doi.org/10.1074/jbc.M114.593392
  45. Moustakas, A. & Heldin, C. H. Non-Smad Tgf-beta signals. J. Cell Sci. 118, 3573-3584 (2005). https://doi.org/10.1242/jcs.02554
  46. Mahajan, V. S. & Pillai, S. Sialic acids and autoimmune disease. Immunol. Rev. 269, 145-161 (2016). https://doi.org/10.1111/imr.12344
  47. Wang, X. et al. Siglec-9 is upregulated in rheumatoid arthritis and suppresses collagen-induced arthritis through reciprocal regulation of Th17-/Treg-cell differentiation. Scand. J. Immunol. 85, 433-440 (2017). https://doi.org/10.1111/sji.12543
  48. O'Sullivan, J. A., Carroll, D. J. & Bochner, B. S. Glycobiology of eosinophilic inflammation: contributions of Siglecs, glycans, and other glycan-binding proteins. Front. Med. (Lausanne) 4, 116 (2017).
  49. Wang, S. et al. Alpha2,6-linked sialic acids on N-glycans modulate the adhesion of hepatocarcinoma cells to lymph nodes. Tumour Biol. 36, 885-892 (2015). https://doi.org/10.1007/s13277-014-2638-x
  50. Belisle, J. A. et al. Identification of siglec-9 as the receptor for Muc16 on human Nk Cells, B cells, and monocytes. Mol. Cancer 9, 118 (2010). https://doi.org/10.1186/1476-4598-9-118
  51. Aalto, K. et al. Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in pet imaging of inflammation and cancer. Blood 118, 3725-3733 (2011).
  52. Crocker, P. R. Siglecs: sialic-acid-binding immunoglobulin-like lectins in cell-cell interactions and signalling. Curr. Opin. Struct. Biol. 12, 609-615 (2002). https://doi.org/10.1016/S0959-440X(02)00375-5
  53. von Gunten, S. et al. Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment. Blood 106, 1423-1431 (2005). https://doi.org/10.1182/blood-2004-10-4112
  54. Eroschenko, V. P. Difiore's Atlas of Histology with Functional Correlations. (Wolters Kluwer Health/Lippincott. Williams & Wilkins, Philadelphia, PA, USA, 2008).
  55. Hull, M. L., Johan, M. Z., Hodge, W. L., Robertson, S. A. & Ingman, W. V. Hostderived Tgfb1 deficiency suppresses lesion development in a mouse model of endometriosis. Am. J. Pathol. 180, 880-887 (2012). https://doi.org/10.1016/j.ajpath.2011.11.013
  56. Correa, L. F. et al. Tgf-beta induces endometriotic progression via a noncanonical, Klf11-mediated mechanism. Endocrinology 157, 3332-3343 (2016). https://doi.org/10.1210/en.2016-1194
  57. Wu, S., Grimm, R., German, J. B. & Lebrilla, C. B. Annotation and structural analysis of sialylated human milk oligosaccharides. J. Proteome Res. 10, 856-868 (2011). https://doi.org/10.1021/pr101006u
  58. Bode, L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 22, 1147-1162 (2012). https://doi.org/10.1093/glycob/cws074
  59. Hill, D. R. & Newburg, D. S. Clinical applications of bioactive milk omponents. Nutr. Rev. 73, 463-476 (2015). https://doi.org/10.1093/nutrit/nuv009
  60. Chung, T. W. et al. Sialyllactose suppresses angiogenesis by inhibiting Vegfr-2 activation, and tumor progression. Oncotarget 8, 58152-58162 (2017).

Cited by

  1. Biological Functions and Analytical Strategies of Sialic Acids in Tumor vol.9, pp.2, 2018, https://doi.org/10.3390/cells9020273
  2. Physiological roles of heteromerization: focus on the two‐pore domain potassium channels vol.599, pp.4, 2018, https://doi.org/10.1113/jp279870
  3. Altered linkage pattern of N-glycan sialic acids in pseudomyxoma peritonei vol.31, pp.3, 2018, https://doi.org/10.1093/glycob/cwaa079
  4. Administration of vitamin E attenuates airway inflammation through restoration of Nrf2 in a mouse model of asthma vol.25, pp.14, 2018, https://doi.org/10.1111/jcmm.16675
  5. Cell‐free culture supernatant of Lactobacillus curvatus Wikim38 inhibits RANKL‐induced osteoclast differentiation and ameliorates bone loss in ovariectomized mice vol.73, pp.3, 2021, https://doi.org/10.1111/lam.13525
  6. A Possible Inhibitory Role of Sialic Acid on MUC1 in Peritoneal Dissemination of Clear Cell-Type Ovarian Cancer Cells vol.26, pp.19, 2021, https://doi.org/10.3390/molecules26195962
  7. Variability of serum IgG sialylation and galactosylation degree in women with advanced endometriosis vol.11, pp.1, 2021, https://doi.org/10.1038/s41598-021-85200-x
  8. Label-free imaging and evaluation of characteristic properties of asthma-derived eosinophils using optical diffraction tomography vol.587, pp.None, 2018, https://doi.org/10.1016/j.bbrc.2021.11.084