Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2016 Mar 16

PMID 26977530

Citations 49

Authors

Yong Song

Jing Fu

Min Zhou

Li Xiao

Xue Feng

Hengxi Chen

Wei Huang

Affiliations

Soon will be listed here.

Abstract

Context: The imbalance in cell proliferation and apoptosis is considered an important role in the pathogenesis of endometriosis, but the exact mechanisms remains unclear. A newly established signaling pathway–Hippo/Yes-associated protein (YAP) pathway plays a critical role in the proliferation and apoptosis processes. However, studies focusing on Hippo/YAP pathway and endometriosis are lacking.

Objective: The objective was to explore the function of the Hippo/YAP pathway in endometriosis.

Setting And Design: The expression of YAP was first investigated in endometrium of women with or without endometriosis. The role of YAP in cell proliferation and apoptosis is identified by transfection of endometrial stromal cells (ESCs) in vitro, subsequent Verteporfin treatments in eutopic ESCs in vitro, and endometriosis animal model of nude mice in vivo.

Results: Our results revealed that increased expression of YAP and decreased expression of p-YAP in ectopic and eutopic endometrium compared with normal endometrium. YAP knockdown in eutopic ESCs decreased cell proliferation and enhanced cell apoptosis companied with decreased expression of TEAD1, CTGF, and B-cell lymphoma/leukemia (BCL)-2; whereas overexpression of YAP resulted in increased proliferation and decreased apoptosis of normal ESCs with increased expression of TEAD1, CTGF, and BCL-2. By chromatin immunoprecipitation qPCR CTGF and BCL-2 were identified as directly downstream target genes of YAP-TEAD1 active complex. Eutopic ESCs treated with Verteporfin revealed decreased proliferation and enhanced apoptosis whereas in endometriosis animal models of nude mice treated with Verteporfin, the size of endometriotic lesions was significantly reduced.

Conclusions: Our study suggests that the Hippo/YAP-signaling pathway plays a critical role in the pathogenesis of endometriosis and should present a novel therapeutic method against endometriosis.

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References

Guo M, Hay B . Cell proliferation and apoptosis. Curr Opin Cell Biol. 1999; 11(6):745-52. DOI: 10.1016/s0955-0674(99)00046-0. View

Wang C, Jin A, Huang W, Tsang L, Cai Z, Zhou X . Up-regulation of Bcl-2 by CD147 Through ERK Activation Results in Abnormal Cell Survival in Human Endometriosis. J Clin Endocrinol Metab. 2015; 100(7):E955-63. DOI: 10.1210/jc.2015-1431. View

Ness R . Endometriosis and ovarian cancer: thoughts on shared pathophysiology. Am J Obstet Gynecol. 2003; 189(1):280-94. DOI: 10.1067/mob.2003.408. View

Beliard A, Noel A, Foidart J . Reduction of apoptosis and proliferation in endometriosis. Fertil Steril. 2004; 82(1):80-5. DOI: 10.1016/j.fertnstert.2003.11.048. View

Ryan I, Schriock E, Taylor R . Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab. 1994; 78(3):642-9. DOI: 10.1210/jcem.78.3.8126136. View

Giudice L, Kao L . Endometriosis. Lancet. 2004; 364(9447):1789-99. DOI: 10.1016/S0140-6736(04)17403-5. View

Szymanowski K . Apoptosis pattern in human endometrium in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol. 2006; 132(1):107-10. DOI: 10.1016/j.ejogrb.2006.04.008. View

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford S . Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007; 130(6):1120-33. PMC: 2666353. DOI: 10.1016/j.cell.2007.07.019. View

Fechner S, Husen B, Thole H, Schmidt M, Gashaw I, Kimmig R . Expression and regulation of estrogen-converting enzymes in ectopic human endometrial tissue. Fertil Steril. 2007; 88(4 Suppl):1029-38. DOI: 10.1016/j.fertnstert.2006.11.153. View

10.

Klemmt P, Carver J, Koninckx P, McVeigh E, Mardon H . Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression. Hum Reprod. 2007; 22(12):3139-47. DOI: 10.1093/humrep/dem262. View

11.

Zhao B, Ye X, Yu J, Li L, Li W, Li S . TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008; 22(14):1962-71. PMC: 2492741. DOI: 10.1101/gad.1664408. View

12.

Park J, Lee J, Kim M, Chang H, Hwang K, Chang K . Endometrium from women with endometriosis shows increased proliferation activity. Fertil Steril. 2009; 92(4):1246-1249. DOI: 10.1016/j.fertnstert.2009.04.025. View

13.

Zhao B, Li L, Lei Q, Guan K . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010; 24(9):862-74. PMC: 2861185. DOI: 10.1101/gad.1909210. View

14.

Yotova I, Quan P, Leditznig N, Beer U, Wenzl R, Tschugguel W . Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis. Hum Reprod. 2011; 26(4):885-97. DOI: 10.1093/humrep/der010. View

15.

Liu-Chittenden Y, Huang B, Shim J, Chen Q, Lee S, Anders R . Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012; 26(12):1300-5. PMC: 3387657. DOI: 10.1101/gad.192856.112. View

16.

Pellegrini C, Gori I, Achtari C, Hornung D, Chardonnens E, Wunder D . The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis. Fertil Steril. 2012; 98(5):1200-8. DOI: 10.1016/j.fertnstert.2012.06.056. View

17.

Abe W, Nasu K, Nakada C, Kawano Y, Moriyama M, Narahara H . miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation and induces apoptosis in endometriotic stromal cells. Hum Reprod. 2013; 28(3):750-61. DOI: 10.1093/humrep/des446. View

18.

Mei J, Li M, Ding D, Li D, Jin L, Hu W . Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway. Int J Clin Exp Pathol. 2013; 6(3):431-44. PMC: 3563200. View

19.

Kawano Y, Nasu K, Hijiya N, Tsukamoto Y, Amada K, Abe W . CCAAT/enhancer-binding protein α is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2013; 98(9):E1474-82. DOI: 10.1210/jc.2013-1608. View

20.

Korkmaz D, Bastu E, Dural O, Yasa C, Yavuz E, Buyru F . Apoptosis through regulation of Bcl-2, Bax and Mcl-1 expressions in endometriotic cyst lesions and the endometrium of women with moderate to severe endometriosis. J Obstet Gynaecol. 2013; 33(7):725-8. DOI: 10.3109/01443615.2013.824416. View