Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology · 2026
SHC1 affects oestrogen-driven differentiation and barrier function of vaginal epithelial cells via EGFR/Ras/ERK pathway.
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Li Jing, Li Juan, Mou Darong, Li Dongyan
Аннотация
BACKGROUND: Vaginal atrophy (VA), a common condition associated with oestrogen deficiency, significantly impacts women's quality of life. Src homology 2 domain-containing transforming protein 1 (SHC1) is implicated in various hormone-dependent processes. This project aims to investigate whether oestrogen promotes the proliferation, migration and differentiation of vaginal epithelial cells by regulating SHC1, and delineates the underlying mechanism.
METHODS: An ovariectomised (OVX) mouse model of VA was established and treated with 17β-estradiol (E2). Human vaginal epithelial VK2/E6E7 cells were stimulated with E2 (dose-dependent), transfected with SHC1 overexpression (OE-SHC1), SHC1 knockdown (sh-SHC1) or epidermal growth factor receptor (EGFR) overexpression (OE-EGFR) plasmids. Histological and immunohistochemical analyses were performed on vaginal tissues. Cellular proliferation and migration were assessed via CCK-8 and wound healing assays, respectively. Western blot analysed cellular/tissue proteins (differentiation/barrier markers, Ras/ERK pathway components).
RESULTS: E2 upregulated SHC1 expression both in atrophic vaginal tissue and in VK2/E6E7 cells in a dose-dependent manner. SHC1 overexpression enhanced, while its knockdown attenuated, E2-induced cell proliferation, migration, and the expression of differentiation (Keratin 6a (krt6a), Keratin 13 (krt13)) and barrier (E-cadherin, occludin) markers. Mechanistically, SHC1 mediated the effects of E2 by acting as an adaptor of EGFR and subsequent activation of the downstream Ras/ERK pathway. EGFR overexpression rescued SHC1 deficiency phenotypes in E2-treated VK2/E6E7 cells. In OVX mice, SHC1 knockdown reversed E2-mediated restoration of vaginal epithelial architecture, proliferation (Ki67) and Ras/ERK signalling.
CONCLUSIONS: SHC1 is a critical mediator of E2-induced vaginal epithelial homeostasis through the EGFR/Ras/ERK axis, representing a potential downstream therapeutic target for intervention in VA, particularly via localised delivery strategies.
METHODS: An ovariectomised (OVX) mouse model of VA was established and treated with 17β-estradiol (E2). Human vaginal epithelial VK2/E6E7 cells were stimulated with E2 (dose-dependent), transfected with SHC1 overexpression (OE-SHC1), SHC1 knockdown (sh-SHC1) or epidermal growth factor receptor (EGFR) overexpression (OE-EGFR) plasmids. Histological and immunohistochemical analyses were performed on vaginal tissues. Cellular proliferation and migration were assessed via CCK-8 and wound healing assays, respectively. Western blot analysed cellular/tissue proteins (differentiation/barrier markers, Ras/ERK pathway components).
RESULTS: E2 upregulated SHC1 expression both in atrophic vaginal tissue and in VK2/E6E7 cells in a dose-dependent manner. SHC1 overexpression enhanced, while its knockdown attenuated, E2-induced cell proliferation, migration, and the expression of differentiation (Keratin 6a (krt6a), Keratin 13 (krt13)) and barrier (E-cadherin, occludin) markers. Mechanistically, SHC1 mediated the effects of E2 by acting as an adaptor of EGFR and subsequent activation of the downstream Ras/ERK pathway. EGFR overexpression rescued SHC1 deficiency phenotypes in E2-treated VK2/E6E7 cells. In OVX mice, SHC1 knockdown reversed E2-mediated restoration of vaginal epithelial architecture, proliferation (Ki67) and Ras/ERK signalling.
CONCLUSIONS: SHC1 is a critical mediator of E2-induced vaginal epithelial homeostasis through the EGFR/Ras/ERK axis, representing a potential downstream therapeutic target for intervention in VA, particularly via localised delivery strategies.