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Decreased Expression of HOXA10 May Activate the Autophagic Process in Ovarian Endometriosis

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Abstract

Autophagy is a survival process that maintains homeostasis in all eukaryotic cells. Recent studies show an abnormal autophagic activity in endometriosis, but the role of autophagy is controversial. Homeobox A10 (HOXA10) is a transcription factor necessary for embryonic and adult uterine development, and studies indicate that its expression decreases in endometriosis. Homeobox A10 may negatively regulate autophagy in endometriosis. To test this hypothesis, we measured the expression levels of autophagic biomarkers (beclin-1 and LC3-II) and HOXA10 proteins by Western blotting and messenger RNA (mRNA) by quantitative real-time polymerase chain reaction. Furthermore, we evaluated the serum cancer antigen 125 (CA125) levels by immunoassay. Most tested autophagic biomarker proteins and mRNAs were upregulated, whereas HOXA10 protein and mRNA were decreased in ovarian endometriomas compared with eutopic endometria of women with endometriosis and normal endometria. Compared with normal endometrium, only protein expression levels of autophagic biomarkers were increased in the eutopic endometrium of women with endometriosis. Moreover, HOXA10 was found to have a significant negative correlation with autophagy (P <.01). Serum CA125 was at a high level in endometriosis and increased with elevated revised American Fertility Society staging (I-IV). There was a significant positive correlation between serum CA125 level and LC3-II protein level and/or LC3-II/LC3-I ratio (P <.01) and a significant negative correlation between serum CA125 level and HOXA10 gene level (P <.01). In conclusion, our studies support that the deficiency of HOXA10 may induce autophagy in endometriosis, and the relationship among CA125, autophagy, and HOXA10 in endometriosis requires additional research.

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References

  1. Bulun SE. Endometriosis. New Eng J Med. 2009;360(3):268–279.

    CAS  PubMed  Google Scholar 

  2. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–275.

    CAS  PubMed  Google Scholar 

  3. Li MQ, Shao J, Meng YH, et al. NME1 suppression promotes growth, adhesion, and implantation of endometrial stromal cells via Akt and MAPK/Erk1/2 signal pathways in the endometriotic milieu. Hum Reprod. 2013;28(10):2822–2831.

    CAS  PubMed  Google Scholar 

  4. Mei J, Zhu XY, Jin LP, Duan ZL, Li DJ, Li MQ. Estrogen promotes the survival of human secretory phase endometrial stromal cells via CXCL12/CXCR4 up-regulation-mediated autophagy inhibition. Hum Reprod. 2015;30(7):1677–1689.

    CAS  PubMed  Google Scholar 

  5. Laschke MW, Giebels C, Menger MD. Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod update. 2011;17(5):628–636.

    CAS  PubMed  Google Scholar 

  6. Pitsos M, Kanakas N. The role of matrix metalloproteinases in the pathogenesis of endometriosis. Reprod Sci. 2009;16(8):717–726.

    CAS  PubMed  Google Scholar 

  7. Harada T, Kaponis A, Iwabe T, et al. Apoptosis in human endometrium and endometriosis. Hum Reprod Update. 2004;10(1):29–38.

    CAS  PubMed  Google Scholar 

  8. Klemmt PA, Carver JG, Kennedy SH, Koninckx PR, Mardon HJ. Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. Fertil Steril. 2006;85(3):564–572.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368(7):651–662.

    CAS  PubMed  Google Scholar 

  10. White E, DiPaola RS. The double-edged sword of autophagy modulation in cancer: an official journal of the American Association for Cancer Research. Clin Cancer Res. 2009;15(17):5308–5316.

    PubMed  PubMed Central  Google Scholar 

  11. Yu JJ, Sun HT, Zhang ZF, et al. IL15 promotes growth and invasion of endometrial stromal cells and inhibits killing activity of NK cells in endometriosis. Reproduction. 2016;152(2):151–160.

    CAS  PubMed  Google Scholar 

  12. Choi J, Jo M, Lee E, Kim HJ, Choi D. Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts. Mol Human Reprod. 2014;20(4):309–317.

    CAS  Google Scholar 

  13. Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F, Maellaro E. Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1. Fertil Steril. 2015;103(5):1244–1251.

    CAS  PubMed  Google Scholar 

  14. Liu H, Zhang Z, Xiong W, et al. Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction. 2017;153(6):809–820.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu TX, Zhao SZ, Dong M, Yu XR. Hypoxia responsive miR-210 promotes cell survival and autophagy of endometriotic cells in hypoxia. Eur Rev Med Pharmacol Sci. 2016;20(3):399–406.

    PubMed  Google Scholar 

  16. Zanatta A, Rocha AM, Carvalho FM, et al. The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review. J Assist Reprod Genet. 2010;27(12):701–710.

    PubMed  PubMed Central  Google Scholar 

  17. Penna I, Du H, Ferriani R, Taylor HS. Calpain5 expression is decreased in endometriosis and regulated by HOXA10 in human endometrial cells. Mol Hum Reprod. 2008;14(10):613–618.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Browne H, Taylor H. HOXA10 expression in ectopic endometrial tissue. Fertil Steril. 2006;85(5):1386–1390.

    CAS  PubMed  Google Scholar 

  19. Chu MC, Selam FB, Taylor HS. HOXA10 regulates p53 expression and matrigel invasion in human breast cancer cells. Cancer Biol Ther. 2004;3(6):568–572.

    CAS  PubMed  Google Scholar 

  20. Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev.Immunol. 2013;13(10):722–737.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–519.

    CAS  PubMed  Google Scholar 

  23. Banreti A, Hudry B, Sass M, Saurin AJ, Graba Y. Hox proteins mediate developmental and environmental control of autophagy. Dev Cell. 2014;28(1):56–69.

    CAS  PubMed  Google Scholar 

  24. Ravikumar B, Sarkar S, Davies JE, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90(4):1383–1435.

    CAS  PubMed  Google Scholar 

  25. Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod. 1997;57(6):1338–1345.

    CAS  PubMed  Google Scholar 

  26. Van Langendonckt A, Luyckx M, Gonzalez MD, Defrere S, Donnez J, Squifflet J. Differential expression of genes from the homeobox a cluster in deep endometriotic nodules and peritoneal lesions. Fertil Steril. 2010;94(6):1995–2000.

    PubMed  Google Scholar 

  27. Lim H, Ma L, Ma WG, Maas RL, Dey SK. Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse. Mol Endocrinol. 1999;13(6):1005–1017.

    CAS  PubMed  Google Scholar 

  28. Du H, Taylor HS. The role of Hox genes in female reproductive tract development, adult function, and fertility. Cold Spring Harb Perspect Med. 2015;6(1):a023002.

    PubMed  Google Scholar 

  29. Andersson KL, Bussani C, Fambrini M, et al. DNA methylation of HOXA10 in eutopic and ectopic endometrium. Hum Reprod. 2014;29(9):1906–1911.

    CAS  PubMed  Google Scholar 

  30. Zhu Y, Li L, Gong S, et al. β3-integrin inhibits lipopolysaccharide-induced autophagy in cardiomyocytes via the Akt signaling pathway. Cardiology. 2015;130(4):249–259.

    CAS  PubMed  Google Scholar 

  31. Meduri G, Guillemeau K, Dounane O, et al. Caspase-cleaved Tau-D(421) is colocalized with the immunophilin FKBP52 in the autophagy-endolysosomal system of Alzheimer’s disease neurons. Neurobiol Aging. 2016;46:124–137.

    CAS  PubMed  Google Scholar 

  32. Petherick KJ, Williams AC, Lane JD, et al. Autolysosomal beta-catenin degradation regulates Wnt-autophagy-p62 crosstalk. EMBO J. 2013;32(13):1903–1916.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rana N, Braun DP, House R, Gebel H, Rotman C, Dmowski WP. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil Steril. 1996;65(5):925–930.

    CAS  PubMed  Google Scholar 

  34. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013;19(4):406–418.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kyama CM, Overbergh L, Debrock S, et al. Increased peritoneal and endometrial gene expression of biologically relevant cytokines and growth factors during the menstrual phase in women with endometriosis. Fertil Steril. 2006;85(6):1667–1675.

    CAS  PubMed  Google Scholar 

  36. McLaren J, Prentice A, Charnock-Jones DS, Smith SK. Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod. 1996;11(1):220–223.

    CAS  PubMed  Google Scholar 

  37. Castello-Cros R, Bonuccelli G, Molchansky A, et al. Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle. 2011;10(12):2021–2034.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sarno J, Schatz F, Huang SJ, Lockwood C, Taylor HS. Thrombin and interleukin-1beta decrease HOX gene expression in human first trimester decidual cells: implications for pregnancy loss. Mol Hum Reprod. 2009;15(7):451–457.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wing LY, Chuang PC, Wu MH, Chen HM, Tsai SJ. Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen. J Clin Endocrinol Metab. 2003;88(11):5547–5554.

    CAS  PubMed  Google Scholar 

  40. Arosh JA, Lee J, Starzinski-Powitz A, Banu SK. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 modulates DNA methylation and histone modification machinery proteins in human endometriotic cells. Mol Cell Endocrinol. 2015;409:51–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee J, Banu SK, Burghardt RC, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits adhesion of human endometriotic epithelial and stromal cells through suppression of integrin-mediated mechanisms. Biol Reprod. 2013;88(3):77.

    PubMed  Google Scholar 

  42. Lee J, Banu SK, Subbarao T, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of human immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases. Mol Cell Endocrinol. 2011;332(1–2):306–313.

    CAS  PubMed  Google Scholar 

  43. Banu SK, Lee J, Speights VO Jr, Starzinski-Powitz A, Arosh JA. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. Mol Endocrinol. 2009;23(8):1291–1305.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Jabbour HN, Sales KJ. Prostaglandin receptor signalling and function in human endometrial pathology. Trends Endocrinol Metab. 2004;15(8):398–404.

    CAS  PubMed  Google Scholar 

  45. Sennlaub F, Valamanesh F, Vazquez-Tello A, et al. Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy. Circulation. 2003;108(2):198–204.

    CAS  PubMed  Google Scholar 

  46. Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell. 2016;166(2):288–298.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mole Cell Biol. 2014;15(2):81–94.

    CAS  Google Scholar 

  48. Morselli E, Shen S, Ruckenstuhl C, et al. p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200. Cell Cycle. 2011;10(16):2763–2769.

    CAS  PubMed  Google Scholar 

  49. Sasaki A, Akita K, Ito F, Mori T, Kitawaki J, Nakada H. Difference in mesothelin-binding ability of serum CA125 between patients with endometriosis and epithelial ovarian cancer. Int J Cancer. 2015;136(8):1985–1990.

    CAS  PubMed  Google Scholar 

  50. Cho S, Park SH, Choi YS, et al. Expression of cyclooxygenase-2 in eutopic endometrium and ovarian endometriotic tissue in women with severe endometriosis. Gynecol obstet invest. 2010;69(2):93–100.

    CAS  PubMed  Google Scholar 

  51. Mihalyi A, Gevaert O, Kyama CM, et al. Non-invasive diagnosis of endometriosis based on a combined analysis of six plasma biomarkers. Hum Reprod. 2010;25(3):654–664.

    CAS  PubMed  Google Scholar 

  52. Kamergorodsky G, Ribeiro PA, Galvao MA, et al. Histologic classification of specimens from women affected by superficial endometriosis, deeply infiltrating endometriosis, and ovarian endometriomas. Fertil Steril. 2009;92(6):2074–2077.

    PubMed  Google Scholar 

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Correspondence to Feiyun Zheng BS.

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Zheng, J., Luo, X., Bao, J. et al. Decreased Expression of HOXA10 May Activate the Autophagic Process in Ovarian Endometriosis. Reprod. Sci. 25, 1446–1454 (2018). https://doi.org/10.1177/1933719118768704

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