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.
Highlights
Adenomyosis (ADS) is a commonly encountered benign gynecological disorder, predominantly occurring in women of reproductive age
On the basis of clarifying the different effects of β-E2 on ADS and normal endometrial cell proliferation, we further demonstrated that a suitable dose of 10 nM β-E2 treatment provided the most significant promoting effects on proliferative rates and colony formative ability, no matter for ADS_Eu_EEC or ADS_Ec_ESC cells (Fig. 1c, d)
Consistent with the functional experiments above, the co-treatment with β-E2 and Fulvestrant partially abolished the overexpression of PCNA and Ki67 induced by β-E2 (Fig. 1e, f). These findings indicated that β-E2 could facilitate ADS endometrial stromal cell proliferation in an ERdependent manner
Summary
Adenomyosis (ADS) is a commonly encountered benign gynecological disorder, predominantly occurring in women of reproductive age. It is typically characterized as the aberrant displacement of eutopic uterine endometrial glands and stroma, deeply and haphazardly involved into myometrium [1]. According to the invagination and EMID (endometrial-myometrial interface disruption) theory [2, 3], ADS may derives from the excessive invasion of altered endometrial basalis into myometrium, after passing through the disrupted EMI. It has been postulated that sustained proliferation and survival of eutopic or ectopic endometrial cells may, along with enhanced migratory prosperities, permit the deeper invasion and down-growth of ectopic lesions [4, 5]. Angiogenesis is considered to be an essential component during the development of ADS, as the implantation of ectopic endometrium requires a blood supply to maintain its growth and survival [6]
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