Estrogen/GPR30 Signaling Contributes to the Malignant Potentials of ER-Negative Cervical Adenocarcinoma via Regulation of Claudin-1 Expression

Abstract

Cervical adenocarcinomas are believed to lose estrogen response on the basis of no expression of a nuclear estrogen receptor such as ERα in clinical pathology. Here, we demonstrated that cervical adenocarcinoma cells respond to a physiological concentration of estrogen to upregulate claudin-1, a cell surface molecule highly expressed in cervical adenocarcinomas. Knockout of claudin-1 induced apoptosis and significantly inhibited proliferation, migration, and invasion of cervical adenocarcinoma cells and tumorigenicity in vivo. Importantly, all of the cervical adenocarcinoma cell lines examined expressed a membrane-bound type estrogen receptor, G protein–coupled receptor 30 (GPR30/GPER1), but not ERα. Estrogen-dependent induction of claudin-1 expression was mediated by GPR30 via ERK and/or Akt signaling. In surgical specimens, there was a positive correlation between claudin-1 expression and GPR30 expression. Double high expression of claudin-1 and GPR30 predicts poor prognosis in patients with cervical adenocarcinomas. Mechanism-based targeting of estrogen/GPR30 signaling and claudin-1 may be effective for cervical adenocarcinoma therapy.

Aldolase A promotes epithelial‐mesenchymal transition to increase malignant potentials of cervical adenocarcinoma

“…In all of the cell lines examined, ALDOA was constitutively expressed (Figure 2A). Among the cell lines, the well‐differentiated type of cervical adenocarcinoma cell line HCA1 was mainly used for subsequent experiments because the cell line retains some epithelial properties, including morphologically intact adherence junctions and tight junctions, and does not carry human herpes viruses 14 …”

“…The human cervical adenocarcinoma cell line CAC‐1 and TMCC‐1 were provided by our colleague Dr Hayakawa 30,31 . Cells were maintained as described previously 14 . Human ALDOA‐specific siRNAs (5′‐GUGUCAUCCUCUUCCAUGA‐3′ and 5′‐GUCAUCCUCUUCCAUGAGA‐3′), human hypoxia‐inducible factor‐1α (HIF‐1α)‐specific siRNAs (5′‐GAAUUACGUUGUGAGUGGU‐3′ and 5′‐GAUUAACUCAGUUUGAACU‐3′) and siRNA universal negative control were purchased from Sigma‐Aldrich.…”

“…The main reasons for the worse prognosis are a higher rate of metastases and resistance to chemoradiotherapy 3 . Consequently, a novel therapeutic strategy is needed to improve the outcome of cervical adenocarcinoma 13‐16 …”

Activation of G Protein-coupled Receptor 30 Promotes Proliferation of Goat Mammary Epithelial Cells via MEK/Erk&PI3K/Akt Signaling Pathway

“…antagonist G36 partly abolished G1-mediated cell proliferation [12]. In addition, estrogen signi cantly enhanced the proliferation of cervical adenocarcinoma cells [24] and endometrial carcinoma cells [8,25] by stimulating GPR30. Intriguingly, GPR30 activation by G1 inhibited the growth of mouse-derived neural stem/progenitor cells, what's more, GPR30 siRNA reversed the inhibitory effect of G1 on cell proliferation [26].…”

“…After stimulation, GPR30 regulates a series of cellular downstream effectors, including EGFR [33,34], adenylyl cyclase [35], cAMP [35], Erk1/2 [36,37], PI3K/Akt [38,39], and others [40,41]. Estrogenic induction of cell proliferation was mediated by GPR30 via Erk/Akt signaling in cervical adenocarcinomas cells [24], on the other hand, an activation in PI3K/Akt and MAPK signaling pathways were also in response to the promotion of bovine mammary epithelial cell survival [39,42]. In addition, in GPR30-positive breast cancer cells, GPR30 activation has been observed to induce rapid activation of Erk1/2 [37], in turn, G15 and knockdown GPR30 caused a reverse [36].…”