P21-Activated Kinase 1 Overactivates in Eutopic Endometrium of Adenomyosis

Adenomyosis is a common gynecological disease, characterized by the existence of endometrium in the myometrium. The pathogenesis of adenomyosis is not fully understood. P21-activated kinase 1 (PAK1) is an effector of small Rho GTPases including CDC42 and RAC1 and plays various roles in cellular biology, especially cytoskeletal remodeling. This study aimed to evaluate whether the expression and activation of PAK1 in adenomyosis were different from normal. Immunohistochemistry was performed to evaluate the expression of PAK1 and its active form phosphorylated-PAK1 (pPAK1) semi-quantitatively in women with and without adenomyosis. Immunofluorescence was performed to locate the distribution of pPAK1. This study found that PAK1 in eutopic endometrium of adenomyosis was overactivated compared to normal. Phosphorylated-PAK1 assembled along the apical surface of glandular cell membrane. In ectopic lesions, PAK1 expression decreased and its activation returned to the baseline. The expression of pPAK1 correlated with the frequency of reproduction. These findings suggest that PAK1 overactivation in the endometrium may be an important event during the development of adenomyosis, meanwhile, decreased phosphorylation may assist to form lesions. Similar content being viewed by others

Struble J, Reid S, Bedaiwy MA. Adenomyosis: a clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol. 2016;23(2):164–185. Levy G, Dehaene A, Laurent N, et al. An update on adenomyosis. Diagn Interv Imaging. 2013;94(1):3–25. Enatsu A, Harada T, Yoshida S, Iwabe T, Terakawa N. Adenomyosis in a patient with the Rokitansky-Kuster-Hauser syndrome. Fertil Steril. 2000;73(4):862–863. Ota H, Igarashi S, Hatazawa J, Tanaka T. Is adenomyosis an immune disease? Hum Reprod Update. 1998;4(4):360–367. Chen YJ, Li HY, Huang CH, et al. Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. J Pathol. 2010;222(3):261–262. Pandis N, Karaiskos C, Bardi G, et al. Chromosome analysis of uterine adenomyosis. Detection of the leiomyoma-associated del(7q) in three cases. Cancer Genet Cytogenet. 1995;80(2):118–120. Kumar R, Sanawar R, Li X, Li F. Structure, biochemistry, and biology of PAK kinases. Gene. 2017;605:20–31. Rane CK, Minden A. P21 activated kinases: structure, regulation, and functions. Small GTPases. 2014;5:e28003. Rane CK, Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2018;1:S1044-579X(17)30249-3. Fife CM, McCarroll JA, Kavallaris M. Movers and shakers: cell cytoskeleton in cancer metastasis. Br J Pharmacol. 2014;171(24):5507–5523. Sens P, Plastino J. Membrane tension and cytoskeleton organization in cell motility. J Phys Condens Matter. 2015;27(27):273103. Liu HY, Leng JH, Sun DW, et al. Comparative proteomics analysis of human adenomyosis. Zhonghua Fu Chan Ke Za Zhi. 2008;43(7):514–517. Jiang J, Sun A, Wang Y, Deng Y. Increased expression of Talin1 in the eutopic and ectopic endometria of women with adenomyosis. Gynecol Endocrinol 2016;32(6):469–472. Kim SR, Kim SH, Lee HW, et al. Increased expression of p21-activated kinase in adenomyosis. Fertil Steril. 2010;94(3):1125–1128. Kim SH, Lee HW, Kim YH, et al. Down-regulation of p21-activated kinase 1 by progestin and its increased expression in the eutopic endometrium of women with endometriosis. Hum Reprod. 2009;24(5):1133–1141. Yi KW, Kim SH, Ihm HJ, et al. Increased expression of p21-activated kinase 4 in adenomyosis and its regulation of matrix metalloproteinase-2 and −9 in endometrial cells. Fertil Steril. 2015;103(4):1089–1097. Herndon CN, Aghajanova L, Balayan S, et al. Global transcriptome abnormalities of the eutopic endometrium from women with adenomyosis. Reprod Sci. 2016;23(10):1289–1303. Martin-Belmonte F, Perez-Moreno M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 2011;12(1):23–38. Koike N, Tsunemi T, Uekuri C, et al. Pathogenesis and malignant transformation of adenomyosis (review). Oncol Rep. 2013;29(3):861–867. Shaked S, Jaffa AJ, Grisaru D, Elad D. Uterine peristalsis-induced stresses within the uterine wall may sprout adenomyosis. Biomech Model Mechanobiol. 2015;14(3):437–444. Cho S, Choi YS, Yun BH, et al. Effects of levonorgestrel-releasing intrauterine system on lymphangiogenesis of adenomyosis. Am J Clin Pathol. 2015;143(3):352–361. Choi YS, Cho S, Lim KJ, et al. Effects of LNG-IUS on nerve growth factor and its receptors expression in patients with adenomyosis. Growth Factors. 2010;28(6):452–460. Yun BH, Jeon YE, Seo SK, et al. Effects of a levonorgestrel-releasing intrauterine system on the expression of steroid receptor coregulators in adenomyosis. Reprod Sci. 2015;22(12):1539–1548. Author information Authors and Affiliations Corresponding author Additional information Authors’ Note Weiwen Zuo and Xiaoyi Wu contributed equally to this work. Rights and permissions About this article Cite this article Zuo, W., Wu, X., Liu, H. et al. P21-Activated Kinase 1 Overactivates in Eutopic Endometrium of Adenomyosis. Reprod. Sci. 26, 1235–1242 (2019). https://doi.org/10.1177/1933719118812737 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719118812737