Restoration of microRNA-29c in type I endometrioid cancer reduced endometrial cancer cell growth.

Endometrial cancer is the most common gynaecological cancer worldwide, and the prognosis of patients with advanced disease remains poor. MicroRNAs (miRs) are dysregulated in endometrial cancer. miRs-29-a, -b and -c expression levels are downregulated in endometrial cancer; however, a specific role for miR-29c and its target genes remain to be elucidated.

miR-29c overexpression and COL4A1 downregulation in infertile human endometrium reduces endometrial epithelial cell adhesive capacity in vitro implying roles in receptivity.

The endometrium is a highly complex tissue that is vulnerable to subtle gene expression changes and is the first point of contact for an implanting blastocyst. Successful blastocyst implantation can only occur when the endometrium is receptive during a short window with each menstrual cycle. microRNAs are small, non-coding RNAs that negatively regulate their gene targets.

Galectin-7 is elevated in endometrioid (type I) endometrial cancer and promotes cell migration.

Endometrial cancer (EC) is the most commonly diagnosed gynecological malignancy in Australian women. Notably, its incidence and mortality rate is increasing. Despite this, there are limited treatment options for EC.

Interleukin 11 blockade during mid to late gestation does not affect maternal blood pressure, pregnancy viability or subsequent fertility in mice.

Interleukin (IL)11 is a crucial regulator during the initiation of pregnancy in humans and mice. Elevated levels are detected in serum, placenta and decidua of women with pre-eclampsia. Elevated IL11 during placentation recapitulates pre-eclampsia in mice, although withdrawal rescues pre-eclampsia features, suggesting that IL11 could provide a novel therapeutic target.

Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity.

Human blastocysts that fail to implant following IVF secrete elevated levels of miR-661, which is taken up by primary human endometrial epithelial cells (HEECs) and impairs their adhesive capability. MicroRNA miR-661 downregulates mouse double minute homologue 2 (MDM2) and MDM4 in other epithelial cell types to activate p53; however, this has not been examined in the endometrium. In this study MDM2 protein was detected in the luminal epithelium of the endometrium, the site of blastocyst attachment, during the mid secretory receptive phase of the menstrual cycle.

Therapeutically blocking Interleukin-11 Receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours.

High grade type I endometrial cancers have poor prognosis. Interleukin (IL)11 is elevated in tumours and uterine lavage with increasing tumour grade in women. IL11 regulates cell cycle, invasion and migration and we recently demonstrated that IL11 receptor (R)α inhibition impaired low and moderate grade endometrial tumourigenesis in vivo.

Chondroitin sulfate proteoglycan protein is stimulated by interleukin 11 and promotes endometrial epithelial cancer cell proliferation and migration.

Endometrial cancer is the most common gynecological cancer. We identified interleukin 11 (IL11) as a critical mediator of endometrial tumourigenesis and demonstrated that IL11 regulates chondroitin sulfate proteoglycan (CSPG4) in human placental trophoblasts. CSPG4 is a cell membrane protein overexpressed in numerous human cancers, although its role in endometrial cancer has not been investigated.

Sexual dimorphism in the glucose homeostasis phenotype of the Aromatase Knockout (ArKO) mice.

We investigated the effects of estrogens on glucose homeostasis using the Aromatase Knockout (ArKO) mouse, which is unable to convert androgens into estrogens. The ArKO mouse is a model of total estrogen ablation which develops symptoms of metabolic syndrome. To determine the development and progression of whole body state of insulin resistance of ArKO mice, comprehensive whole body tolerance tests were performed on WT, ArKO and estrogen administrated mice at 3 and 12 months of age.

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo.

Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. IL11 is a cytokine that regulates cell cycle, invasion, and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumors and uterine lavage fluid in women with endometrial cancer, and alters endometrial epithelial cancer cell adhesion and migration in vitro, but its role in endometrial tumorigenesis in vivo is unknown.

Interleukin-11 alters placentation and causes preeclampsia features in mice.

Preeclampsia (PE) is a pregnancy-specific disorder characterized by hypertension and proteinuria after 20 wk gestation. Abnormal extravillous trophoblast (EVT) invasion and remodeling of uterine spiral arterioles is thought to contribute to PE development. Interleukin-11 (IL11) impedes human EVT invasion in vitro and is elevated in PE decidua in women.

Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion.

Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome.

Soluble Delta-like ligand 1 alters human endometrial epithelial cell adhesive capacity.

The endometrium undergoes substantial morphological and functional changes to become receptive to embryo implantation and to enable establishment of a successful pregnancy. Reduced Delta-like ligand 1 (DLL1, Notch ligand) in the endometrium is associated with infertility. DLL1 can be cleaved by 'a disintegrin and metalloprotease' (ADAM) proteases to produce a soluble ligand that may act to inhibit Notch signalling.

Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.

The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism.

Interleukin 11: similar or opposite roles in female reproduction and reproductive cancer?

During placental development and carcinogenesis, cell invasion and migration are critical events in establishing a self-supporting vascular supply. Interleukin (IL)-11 is a pleiotropic cytokine that affects the invasive and migratory capabilities of trophoblast cells that form the placenta during pregnancy, as well as various malignant cell types. The endometrium is the site of embryo implantation during pregnancy; conversely, endometrial carcinoma is the most common gynaecological malignancy.

Localisation of the Notch family in the human endometrium of fertile and infertile women.

To investigate the spatial and temporal immunolocalisation and staining intensity of the Notch signalling family in endometrium of fertile and infertile women, endometrial biopsies were collected by curettage from 25 fertile women across the menstrual cycle and 10 infertile women in the mid secretory phase of menstrual cycle. Immunohisotchemistry was completed for NOTCH1, -2, -3, -4, cleaved Notch, DLL1, -3, -4, JAGGED1, -2, HES and NUMB and immunostaining intensity measured in both the endometrial glandular and luminal epithelium. NOTCH1 and the ligands DLL1 and JAGGED1 were key proteins displaying increased staining intensity during the receptive phase of the menstrual cycle and dysregulated in infertile endometrium.

Hepatic glucose intolerance precedes hepatic steatosis in the male aromatase knockout (ArKO) mouse.

Estrogens are known to play a role in modulating metabolic processes within the body. The Aromatase knockout (ArKO) mice have been shown to harbor factors of Metabolic syndrome with central adiposity, hyperinsulinemia and male-specific hepatic steatosis. To determine the effects of estrogen ablation and subsequent replacement in males on whole body glucose metabolism, three- and six-month-old male ArKO mice were subjected to whole body glucose, insulin and pyruvate tolerance tests and analyzed for ensuing metabolic changes in liver, adipose tissue, and skeletal muscle.

Fetal-maternal communication: the role of Notch signalling in embryo implantation.

The establishment of a successful pregnancy requires the implantation of a competent blastocyst into a 'receptive' endometrium, facilitating the formation of a functional placenta. Inadequate or inappropriate implantation and placentation is a major reason for infertility and is thought to lead to first-trimester miscarriage, placental insufficiency and other obstetric complications. Blastocyst-endometrial interactions are critical for implantation and placental formation.

Corin, an enzyme with a putative role in spiral artery remodeling, is up-regulated in late secretory endometrium and first trimester decidua.

Study Question: What is the nature of cellular Corin expression in human gestational tissues?

Summary Answer: CORIN is expressed in non-pregnant late secretory phase endometrium, first trimester human implantation sites and is up-regulated with decidualization ex vivo.

What Is Known Already: Adequate trophoblast invasion and spiral artery remodeling/transformation is critical for successful implantation. CORIN, best known for its role in activating atrial natruietic peptide (ANP) to regulate blood pressure, has recently been proposed to be centrally involved in trophoblast invasion and spiral artery remodeling.

Preimplantation human blastocyst-endometrial interactions: the role of inflammatory mediators.

Immune factors such as cytokines, chemokines, and growth factors are known to play important roles in the preimplantation interactions and communication between the blastocyst and receptive endometrium. This crucial dialog occurs during the stages when the blastocyst is in the uterine cavity immediately preceding implantation and the establishment of pregnancy. Human preimplantation processes are difficult to study due to restrictions on tissue availability.

Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo.

Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary.

Differential effect of amphetamine on c-fos expression in female aromatase knockout (ArKO) mice compared to wildtype controls.

Estrogen may be involved in psychosis by an interaction with central dopaminergic activity. Aromatase knockout mice are unable to produce estrogen and have been shown to display altered behavioural responses and effects of the dopamine releaser, amphetamine. This study investigates the effect of gonadal status on amphetamine-induced c-fos expression in the brains of female aromatase knockout and wildtype mice.

The estrogenic component of tibolone reduces adiposity in female aromatase knockout mice.

Objective: To explore the effects of tibolone on adiposity in the absence of aromatase and determine which of the hormonal properties of tibolone are exerting these effects.

Methods: In this study, vehicle; tibolone; estrogenic (ethinyl estradiol [EE]), progestogenic (ORG2058), or androgenic (dihydrotestosterone) compounds; or a combination of ORG2058 + EE was administered to 6-month-old ovariectomized aromatase knockout (ArKO) mice for a period of 6 weeks.

Results: In response to tibolone or EE-alone treatments, omental adipose tissue and infrarenal adipose tissue weights were significantly reduced (P = 0.