miR-423-3p inhibits CTNNBIP1/WNT preventing hyperandrogenic PCOS.

Polycystic ovary syndrome (PCOS) lacks the generally accepted diagnostic biomarkers and targeted therapy. Increasing evidence indicates that microRNAs (miRNAs) play a crucial role in PCOS. Hereby, we tested the functional implications of a novel miRNA (miR-423-3p) as a mediator in the progress of hyperandrogenic PCOS, as well as its potential as a new serum biomarker and therapeutic target for the PCOS.

Targeted destruction of follicle stimulating hormone receptor-positive cancer cells in vitro and in vivo by a lytic peptide Phor21-FSHβ conjugate.

Background: Extragonadal follicle-stimulating hormone (FSH) receptor (FSHR) expression in various cancers and their endothelial vessel cells has highlighted novel opportunities for targeted FSHR therapy.

Methods: We investigated the specificity/cytotoxicity of Phor21 fusion lytic peptide, conjugated to 12 different FSHβ-chain fragments to ablate FSHR-expressing cancer cells in vitro and Additionally, the use of the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix (CTX) alone or with the Phor21-FSHβ33-53 C/S conjugate for anticancer therapy was analyzed.

Results: Phor21 linked to the FSHβ33–53 fragment with cysteine (Cys) replaced by serine (Ser) (Phor21-FSHβ33-53 C/S) demonstrated the highest specific cytotoxicity towards FSHR possessing cancer cells vs.

CD8 T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells.

T cells and their effector functions, in particular the canonical cytotoxicity of CD8 T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8 T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8 T cells expressed CD40L, and conditional CD40L ablation in CD8 T cells alone led to tumor formation.

Hecate-FSHβ33-53C/S lytic peptide conjugate selectively kills targeted follicle stimulating hormone receptor (FSHR)-positive cancer cells.

Background: The follicle stimulating hormone (FSH) receptor (FSHR), is expressed primarily in the gonads, also found in ovarian and prostate cancers, and in tumor vessel endothelial cells. We investigated the potential of a targeted cytotoxic approach using Hecate-FSHβ, a conjugate derived from a lytic peptide Hecate, an analog of bee venom melittin, and the β subunit of FSH, to selectively eliminate FSHR-positive cancer cells.

Methods: Hecate-FSHβ-mediated cytotoxicity was tested in human granulosa tumor cell line KGN, human embryonic kidney HEK-293 cell line stably transfected with human FSHR cDNA (HEK293-FSHR) and mock-transfected HEK-293 cells as FSHR-negative control cells.

Novel ectopic expression of zona pellucida 3 glycoprotein in lung cancer promotes tumor growth.

Zona pellucida 3 (ZP3) expression is classically found in the ZP-layer of the oocytes, lately shown in ovarian and prostate cancer. A successful ZP3 ovarian cancer immunotherapy in transgenic mice suggested its use as an attractive therapeutic target. The biological role of ZP3 in cancer growth and progression is still unknown.

Functional evidence for two distinct mechanisms of action of progesterone and selective progesterone receptor modulator on uterine leiomyomas.

Objective: To study the specific mechanisms through which progesterone and selective progesterone receptor modulators impact the growth, synthesis, and accumulation of the extracellular matrix in uterine leiomyomas.

Design: Laboratory study.

Setting: Academic Research Institutions.

Progesterone signaling in uterine leiomyoma biology: Implications for potential targeted therapy.

Uterine leiomyomas (ULs) are the most common benign smooth muscle cell steroid-dependent tumors that occur in women of reproductive age. Progesterone (P4) is a major hormone that promotes the ULs development and growth. P4 action in ULs is mediated mainly by its nuclear progesterone receptors (PGRs), although rapid non-genomic responses have also been observed.

Serum expression levels of selected microRNAs and their association with glucose metabolism in young women with polycystic ovary syndrome.

Introduction: Polycystic ovary syndrome (PCOS) is associated with metabolic disturbances, such as insulin resistance and prediabetes, and the risk for their occurrence is especially increased in hyperandrogenic (HA) phenotypes of PCOS. Circulating microRNAs (miRNAs) may be involved in PCOS pathogenesis and regulation of metabolic processes.

Objectives: The aim of the study was to assess expression levels of selected circulating miRNAs in women with PCOS and to investigate the relationship of these miRNAs with glucose metabolism.

New Insights on the Progesterone (P4) and PGRMC1/NENF Complex Interactions in Colorectal Cancer Progression.

The literature data regarding the risk of colorectal cancer (CRC) in the context of hormone therapy (HT), including both estrogen-progestogen combinations and estrogen alone, are inconclusive. The precise relationship underlying the action of progesterone (P4) and progesterone receptors in CRC has yet to be determined. We characterized the expression profiles of both nuclear and membrane progesterone receptors and their potential cofactors in CRC tissues.

The molecular mechanism of miR-96-5p in the pathogenesis and treatment of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), characterized by the androgen excess and arrest of antral follicles, is a common endocrine disorder among women lacking specific diagnostic biomarkers and therapeutic targets. Herein, we studied the molecular mechanism of miR-96-5p in the process of PCOS and its potential applications in PCOS. Clinically, we found that miR-96-5p significantly decreased in serum, follicular fluid and primary human granulosa cells (hGCs) of PCOS patients (n = 70) vs non-PCOS women (n = 60), as well as in the ovaries of 3-types of induced PCOS-like mice.

Functional Implications of Estrogen and Progesterone Receptors Expression in Adenomyosis, Potential Targets for Endocrinological Therapy.

Adenomyosis is a common gynaecological disease associated with the presence of endometrial lesions in the uterine myometrium. Estrogens have been proven to be the crucial hormones driving the growth of adenomyosis. Little is known about the distinct mechanisms of progesterone action in adenomyosis.

Role and mechanism of miR-335-5p in the pathogenesis and treatment of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown etiology that occurs in women of reproductive age. Despite being considered to affect up to one-fifth of women in this cohort, the condition lacks generally accepted diagnostic biomarkers and options for targeted therapy. Hereby, we analyzed the diagnostic, therapeutic, and functional potential of a recently discovered miR-335-5p that was observed to be reduced in the follicular fluid (FF) of PCOS patients as compared with healthy women.

The Association between Bisphenol A, Steroid Hormones, and Selected MicroRNAs Levels in Seminal Plasma of Men with Infertility.

Bisphenol A (BPA), the most common endocrine-disrupting chemical, has been associated with male reproductive dysfunctions. Recently, it has been shown that BPA may also affect miRNAs expression. Herein, we aimed to evaluate the association of BPA levels with steroid hormone concentration and circulating miRNAs levels to investigate the potential direct effect of BPA on homeostasis in the testis environment.

Novel expression of zona pellucida 3 protein in normal testis; potential functional implications.

The expression of the zona pellucida glycoprotein 3 (ZP3), originally thought to be specific for oocytes, was recently extended to ovarian, prostate, colorectal and lung cancers. Earlier successful ZP3 immunization of a transgenic mouse model carrying a ZP3 positive ovarian tumor emphasized the suitability of ZP3 for cancer immunotherapy. This study was carried out to determine whether any other normal tissues besides the ovary in healthy human and mouse tissues may express ZP3, considered important to exclude off-target effects of ZP3 cancer immunotherapy.

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro.

Cyanidin-3-o-Glucoside Pharmacologically Inhibits Tumorigenesis via Estrogen Receptor β in Melanoma Mice.

Expression patterns of estrogen receptors [ERα, ERβ, and G-protein associated ER (GPER)] in melanoma and skin may suggest their differential roles in carcinogenesis. Phytoestrogenic compound cyanidin-3-o-glucoside (C3G) has been shown to inhibit the growth and metastatic potential of melanoma, although the underlying molecular mechanism remains unclear. The aim of this study was to clarify the mechanism of action of C3G in melanoma and , as well as to characterize the functional expressions of ERs in melanoma.

Oxytocin antagonism reverses the effects of high oestrogen levels and oxytocin on decidualization and cyclooxygenase activity in endometrial tissues.

Research Question: What is the in-vitro effect of oxytocin receptor (OTR) antagonism on parameters of receptivity in human endometrial explants and endometrial stromal cell lines cultured in oestradiol-rich conditions mimicking ovarian stimulation?

Design: Experimental in-vitro study on endometrial tissue explants collected by aspiration biopsy from 30 women undergoing fertility treatment and cultured endometrial tHESC cell line. The study examined the effects of high oestradiol, oxytocin and OTR antagonist on parameters of decidualization (cell viability and prolactin secretion) as well as cyclooxygenase-1/2 (COX-1/2) activity and prostaglandin F (PGF) secretion. Changes in expression of OXTR and COX-2 genes were examined using quantitative polymerase chain reaction (qPCR).

Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression.

Background: Recent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function.

Methods: Ovarian cancer human and murine cell lines, cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess the molecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression.

Findings: Herein, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abundantly P4 receptor membrane component 1 (PGRMC1).

Extragonadal FSHR Expression and Function-Is It Real?

Expression of the follicle-stimulating hormone receptor (FSHR), besides gonadal tissues, has recently been detected in several extragonadal normal and tumorous tissues, including different types of primary and metastatic cancer and tumor vessel endothelial cells (TVEC). The suggested FSH actions in extragonadal tissues include promotion of angiogenesis, myometrial contractility, skeletal integrity, and adipose tissue accumulation. Non-malignant cells within cancer tissue have been shown to be devoid of FSHR expression, which implies a potential role of FSHR as a diagnostic, prognostic, or even a therapeutic tool.

Revisiting the expression and function of follicle-stimulation hormone receptor in human umbilical vein endothelial cells.

Expression of follicle-stimulation hormone receptor (FSHR) is confined to gonads and at low levels to some extragonadal tissues like human umbilical vein endothelial cells (HUVEC). FSH-FSHR signaling was shown to promote HUVEC angiogenesis and thereafter suggested to have an influential role in pregnancy. We revisited hereby the expression and functionality of FSHR in HUVECs angiogenesis, and were unable to reproduce the FSHR expression in human umbilical cord, HUVECs or immortalized HUVECs (HUV-ST).

Functional Expression of FSH Receptor in Endometriotic Lesions.

Context: FSH receptor (FSHR), besides being expressed in gonads, is also expressed in some extragonadal tissues at low levels.

Objective: We examined the functional expression of FSHR in different types of endometriotic lesions.

Design: Extensive studies were carried out to detect functional FSHR expression and FSH-stimulated estrogen production in ovarian endometriomas and recto-vaginal endometriotic nodules (RVEN).

Contrasting genetic structure of rear edge and continuous range populations of a parasitic butterfly infected by Wolbachia.

Background: Climatic oscillations are among the long-term factors shaping the molecular features of animals and plants and it is generally supposed that the rear edges (i.e., the low-latitude limits of distribution of any given specialised species) situated closer to glacial refugia are vital long-term stores of genetic diversity.