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Activation of the CXCL16/CXCR6 Axis by TNF-α Contributes to Ectopic Endometrial Stromal Cells Migration and Invasion

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Abstract

The activation of systemic and local inflammatory mechanisms, including elevated levels of chemokines and proinflammatory cytokines in endometriosis progression, is becoming more evident in the recent years. Here, we report the involvement of CXC chemokine 16 (CXCL16) and its sole receptor, CXC chemokine receptor 6 (CXCR6), in pathophysiology of endometriosis. Expression of CXCL16, but not CXCR6, was significantly upregulated in endometriotic lesions when compared to control endometrium. Additionally, serum CXCL16 was significantly elevated in women with endometriosis when compared to control group. Moreover, blockade of the CXCL16/CXCR6 axis by CXCR6 small-interfering RNA reduced the migration and invasion of ectopic endometrial stromal cells (EESCs) followed by decreased phosphorylation of ERK1/2. Furthermore, TNF-α treatment induced the expression of CXCL16 in EESCs. In conclusion, these results suggest that CXCL16/CXCR6 axis, whose expression was enhanced by TNF-α, may be associated with the increased motility of EESCs, through regulation of ERK1/2 signaling, thus contributing to the development of endometriosis. These findings indicate that the CXCL16/CXCR6 axis may contribute to the progression of endometriosis and could be served as a potential target for diagnosis and treatment.

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Reference

  1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.

    PubMed  Google Scholar 

  2. Culley L, Law C, Hudson N, et al. The social and psychological impact of endometriosis on women’s lives: a critical narrative review. Hum Reprod Update. 2013;19(6):625–639.

    Article  PubMed  Google Scholar 

  3. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.

    CAS  PubMed  Google Scholar 

  4. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  5. Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. Inflammation in reproductive disorders. Reprod Sci. 2009;16(2):216–229.

    Article  CAS  PubMed  Google Scholar 

  6. Ulukus M, Arici A. Immunology of endometriosis. Minerva Ginecol. 2005;57(3):237–248.

    CAS  PubMed  Google Scholar 

  7. Akoum A, Lemay A, McColl S, Turcot-Lemay L, Maheux R. Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis. Fertil Steril. 1996;66(1):17–23.

    Article  CAS  PubMed  Google Scholar 

  8. Akoum A, Kong J, Metz C, Beaumont MC. Spontaneous and stimulated secretion of monocyte chemotactic protein-1 and macrophage migration inhibitory factor by peritoneal macrophages in women with and without endometriosis. Fertil Steril. 2002;77(5):989–994.

    Article  PubMed  Google Scholar 

  9. Ramey JW, Archer DF. Peritoneal fluid: its relevance to the development of endometriosis. Fertil Steril. 1993;60(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  10. Wu M-Y, Ho H-N. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296.

    Article  PubMed  Google Scholar 

  11. Iwabe T, Harada T, Tsudo T, et al. Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab. 2000;85(2):824–829.

    CAS  PubMed  Google Scholar 

  12. Eisermann J, Gast MJ, Pineda J, Odem RR, Collins JL. Tumor necrosis factor in peritoneal fluid of women undergoing laparoscopic surgery. Fertil Steril. 1988;50(4):573–579.

    Article  CAS  PubMed  Google Scholar 

  13. D’Antonio M, Martelli F, Peano S, Papoian R, Borrelli F. Ability of recombinant human TNF binding protein-1 (r-hTBP-1) to inhibit the development of experimentally-induced endometriosis in rats. J Reprod Immunol. 2000;48(2):81–98.

    Article  PubMed  Google Scholar 

  14. Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, Propst AM. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril. 2004;81(suppl 1):775–779.

    Article  CAS  PubMed  Google Scholar 

  15. Koizumi K, Hojo S, Akashi T, Yasumoto K, Saiki I. Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Sci. 2007;98(11):1652–1658.

    Article  CAS  PubMed  Google Scholar 

  16. Luster AD. Chemokines‐‐chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338(7):436–445.

    Article  CAS  PubMed  Google Scholar 

  17. Struyf S, Proost P, Van Damme J. Regulation of the immune response by the interaction of chemokines and proteases. Adv Immunol. 2003;81:1–44.

    Article  CAS  PubMed  Google Scholar 

  18. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217–242.

    Article  CAS  PubMed  Google Scholar 

  19. Arici A, Tazuke SI, Attar E, Kliman HJ, Olive DL. Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells. Mol Hum Reprod. 1996;2(1):40–45.

    Article  CAS  PubMed  Google Scholar 

  20. Ruiz A, Salvo VA, Ruiz LA, Báez P, García M, Flores I. Basal and steroid hormone-regulated expression of CXCR4 in human endometrium and endometriosis. Reprod Sci. 2010;17(10):894–903.

    Article  CAS  PubMed  Google Scholar 

  21. Hu W, Zhen X, Xiong B, Wang B, Zhang W, Zhou W. CXCR6 is expressed in human prostate cancer in vivo and is involved in the in vitro invasion of PC3 and LNCap cells. Cancer Sci. 2008;99(7):1362–1369.

    Article  CAS  PubMed  Google Scholar 

  22. Xiao G, Wang X, Wang J, et al. CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms. Oncotarget. 2015;6(16).

  23. Hald SM, Kiselev Y, Al-Saad S, et al. Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival. BMC Cancer. 2015;15(1):11.

    Article  Google Scholar 

  24. Jin J-J, Dai F-X, Long Z-W, et al. CXCR6 predicts poor prognosis in gastric cancer and promotes tumor metastasis through epithelial-mesenchymal transition. Oncol Rep. 2017;37(6):3279–3286.

    Article  PubMed  Google Scholar 

  25. Manabe S, Iwase A, Goto M, et al. Expression and localization of CXCL16 and CXCR6 in ovarian endometriotic tissues. Arch Gynecol Obstet. 2011;284(6):1567–1572.

    Article  CAS  PubMed  Google Scholar 

  26. Zhan H, Ma J, Ruan F, et al. Elevated phosphatase of regenerating liver 3 (PRL-3) promotes cytoskeleton reorganization, cell migration and invasion in endometrial stromal cells from endometrioma. Hum Reprod. 2016;31(4):723–733.

    Article  CAS  PubMed  Google Scholar 

  27. Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Invasiveness of endometriotic cells in vitro. Lancet. 1995;346(8988):1463–1464.

    Article  CAS  PubMed  Google Scholar 

  28. Yu T, Wu Y, Helman JI, Wen Y, Wang C, Li L. CXCR4 promotes oral squamous cell carcinoma migration and invasion through inducing expression of MMP-9 and MMP-13 via the ERK signaling pathway. Mol Cancer Res. 2011;9(2):161–172.

    Article  CAS  PubMed  Google Scholar 

  29. Lin F, Chengyao X, Qingchang L, Qianze D, Enhua W, Yan W. CRKL promotes lung cancer cell invasion through ERK-MMP9 pathway. Mol Carcinog. 2015;54(Suppl 1): E35–E44.

    Article  PubMed  Google Scholar 

  30. McCawley LJ, Li S, Wattenberg EV, Hudson LG. Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. J Biol Chem. 1999;274(7):4347–4353.

    Article  CAS  PubMed  Google Scholar 

  31. Abel S, Hundhausen C, Mentlein R, et al. The transmembrane CXC-chemokine ligand 16 is induced by IFN- and TNF- and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol. 2004;172(10):6362–6372.

    Article  CAS  PubMed  Google Scholar 

  32. Khorram O, Taylor RN, Ryan IP, Schall TJ, Landers DV. Peritoneal fluid concentrations of the cytokine RANTES correlate with the severity of endometriosis. Am J Obstet Gynecol. 1993;169(6):1545–1549.

    Article  CAS  PubMed  Google Scholar 

  33. Borrelli GM, Carvalho KI, Kallas EG, Mechsner S, Baracat EC, Abrao MS. Chemokines in the pathogenesis of endometriosis and infertility. J Reprod Immunol. 2013;98(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  34. Lu Y, Wang J, Xu Y, et al. CXCL16 functions as a novel chemotactic factor for prostate cancer cells in vitro. Mol Cancer Res. 2008;6(4):546–554.

    Article  CAS  PubMed  Google Scholar 

  35. Wagsater D, Hugander A, Dimberg J. Expression of CXCL16 in human rectal cancer. Int J Mol Med. 2004;14(1):65–69.

    PubMed  Google Scholar 

  36. Gutwein P, Schramme A, Sinke N, et al. Tumoural CXCL16 expression is a novel prognostic marker of longer survival times in renal cell cancer patients. Eur J Cancer. 2009;45(3):478–489.

    Article  CAS  PubMed  Google Scholar 

  37. Wente MN, Gaida MM, Mayer C, et al. Expression and potential function of the CXC chemokine CXCL16 in pancreatic ductal adenocarcinoma. Int J Oncol. 2008;33(2):297–308.

    CAS  PubMed  Google Scholar 

  38. Seidl H, Richtig E, Tilz H, et al. Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma. Human Pathol. 2007;38(5):768–780.

    Article  CAS  Google Scholar 

  39. Maekawa M, Ishizaki T, Boku S, et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999;285(5429):895–898.

    Article  CAS  PubMed  Google Scholar 

  40. Chen T, Guo Z-P, Jiao X-Y, et al. Peoniflorin suppresses tumor necrosis factor-α induced chemokine production in human dermal microvascular endothelial cells by blocking nuclear factor-κB and ERK pathway. Arch Dermatol Res. 2010;303(5):351–360.

    Article  PubMed  Google Scholar 

  41. Chandrasekar B, Bysani S, Mummidi S. CXCL16 signals via Gi, phosphatidylinositol 3-kinase, Akt, I kappa B kinase, and nuclear factor-kappa B and induces cell-cell adhesion and aortic smooth muscle cell proliferation. J Biol Chem. 2004;279(5):3188–3196.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Women’s Hospital, Zhejiang University Medical College, Hangzhou, 310006, People’s Republic of China

    Yaoming Peng MM & Jun Lin MD

  2. Key Laboratory of women’s Reproductive Health of Zhejiang Province, Hangzhou, People’s Republic of China

    Junyan Ma MD

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  1. Yaoming Peng MM
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  2. Junyan Ma MD
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  3. Jun Lin MD
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Correspondence to Jun Lin MD.

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Author’s Note

Junyan Ma is co-first author on this work.

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Peng, Y., Ma, J. & Lin, J. Activation of the CXCL16/CXCR6 Axis by TNF-α Contributes to Ectopic Endometrial Stromal Cells Migration and Invasion. Reprod. Sci. 26, 420–427 (2019). https://doi.org/10.1177/1933719118776797

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