Upregulated Talin1 synergistically boosts β-estradiol-induced proliferation and pro-angiogenesis of eutopic and ectopic endometrial stromal cells in adenomyosis

Abstract

Adenomyosis (ADS) is an estrogen-dependent gynecological disease with unspecified etiopathogenesis. Local hyperestrogenism may serve a key role in contributing to the origin of ADS. Talin1 is mostly identified to be overexpressed and involved in the progression of numerous human carcinomas through mediating cell proliferation, adhesion and motility. Whether Talin1 exerts an oncogenic role in the pathogenesis of ADS and puts an extra impact on the efficacy of estrogen, no relevant data are available yet. Here we demonstrated that the adenomyotic eutopic and ectopic endometrial stromal cells (ADS_Eu_ESC and ADS_Ec_ESC) treated with β-estradiol (β-E2) presented stronger proliferative and pro-angiogenetic capacities, accompanied by increased expression of PCNA, Ki67, VEGFB and ANGPTL4 proteins. Meanwhile, these promoting effects were partially abrogated by Fulvestrant (ICI 182780, an estrogen-receptor antagonist). Aberrantly upregulation of Talin1 mRNA and protein level was observed in ADS endometrial specimens and stromal cells. Through performing functional experiments in vitro, we further determined that merely overexpression of Talin1 (OV-Talin1) also enhanced ADS stromal cell proliferation and pro-angiogenesis, while the most pronounced facilitating effects were found in the co-intervention group of OV-Talin1 plus β-E2 treatment. Results from the xenograft nude mice model showed that the hypodermic endometrial lesions from co-intervention group had the highest mean weight and volume, compared with that of individual OV-Talin1 or β-E2 treatment. The expression levels of PCNA, Ki67, VEGFB and ANGPTL4 in the lesions were correspondingly elevated the most in the co-intervention group. Our findings unveiled that overexpressed Talin1 might cooperate withβ-E2 in stimulating ADS endometrial stromal cell proliferation and neovascularization, synergistically promoting the growth and survival of ectopic lesions. These results may be beneficial to provide a new insight for clarifying the pathogenesis of ADS.

Estradiol mediates the interaction of LINC01541 and miR-429 to promote angiogenesis of G1/G2 endometrioid adenocarcinoma in-vitro: A pilot study

“…In another study, E2 treatment of endometrial stromal cells was demonstrated to be more angiogenic and associated with increased VEGFB protein expression. Meanwhile, these stimulants can be were partially eliminated by an estrogen-receptor antagonist (45). In the current study, miR-200s (except miR-200c) were shown to interact with LINC01541.…”

Transcriptome analysis of eutopic endometrial stromal cells in women with adenomyosis by RNA-sequencing

“…It has also been shown that angiogenesis participates in the pathophysiology of abnormal uterine bleeding and subfertility in AM [ 48 ]. Wang et al demonstrated that A-EuESCs treated with β-estradiol presented stronger pro-angiogenetic capacities, accompanied by the increased expression levels of VEGFB and ANGPTL4 proteins [ 14 ]. Furthermore, our chord plot analysis revealed that upregulated genes of FOXC2, TLR3, GATA6, HGF, IL-6, PTK2B, ANGPTL4 , and HIF1A were involved in the regulation of angiogenesis ( Figure 5 ).…”

“…Recent studies have suggested that a heritable or acquired alteration in the eutopic endometrium may play an essential role in the occurrence of AM [ 9–12 ]. Eutopic endometrium of the women with AM showed abnormal biological processes, including decreased apoptosis [ 8 , 13 ], increased proliferation [ 10 ] and angiogenesis [ 14 ], and impaired cytokine expression and local production of estrogens, which involved the pathogenesis of AM by enhancing the infiltration of the endometrium to the junctional zone and the growth of ectopic tissue [ 15 ]. Numerous AM-based studies have concentrated on the eutopic endometrium.…”

“…In addition, both exogenous and endogenous interleukin-22 (IL-22) have enhanced the invasiveness of A-EuESCs in vitro [ 21 ]. Besides, A-EuESCs were proliferated more rapidly than normal endometrial stromal cells (N-ESCs), whether they were treated with or without estradiol (E2), medroxyprogesterone acetate (MPA), interleukin 6 (IL-6), lipopolysaccharide (LPS) and interferon γ (IFN-γ) [ 10 , 14 ]. A-EuECSs also expressed a higher level of AMP-activated protein kinase (AMPK) than N-ESCs [ 22 ].…”

Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists

“…It is widely known that estrogen exerts a proliferative effect on the endometrium, while adenomyosis has been repeatedly associated with endometrial cell overproliferation [ 28 ]. Indeed, a recent study demonstrated that supplementing culture of endometrial stromal cells from adenomyosis patients with estradiol (E2) significantly boosted their proliferation rates [ 29 ]. In addition to proliferation, estrogen has been shown to induce EMT in adenomyosis, a phenomenon frequently blamed for endometrial invasiveness [ 16 , 30 ].…”