Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

Background  

Interleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines.     

Vascular endothelial growth factor-D over-expressing tumor cells induce differential effects on uterine vasculature in a mouse model of endometrial cancer

Background  

It has been hypothesised that increased VEGF-D expression may be an independent prognostic factor for endometrial cancer progression and lymph node metastasis; however, the mechanism by which VEGF-D may promote disease progression in women with endometrial cancer has not been investigated. Our aim was to describe the distribution of lymphatic vessels in mouse uterus and to examine the effect of VEGF-D over-expression on these vessels in a model of endometrial cancer. We hypothesised that VEGF-D over-expression would stimulate growth of new lymphatic vessels into the endometrium, thereby contributing to cancer progression.     

Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b

Background  

Coordinated differentiation of the endometrial compartments in the second half of the menstrual cycle is a prerequisite for the establishment of pregnancy. Endometrial stromal cells (ESC) decidualize under the influence of ovarian progesterone to accommodate implantation of the blastocyst and support establishment of the placenta. Studies into the mechanisms of decidualization are often hampered by the lack of primary ESC. Here we describe a novel immortalized human ESC line.     

Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer

Background

Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).

Methodology and Principal Findings

Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa(IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB(IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.

Conclusion

Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.     

Gene expression profiling predicts a three-gene expression signature of endometrial adenocarcinoma in a rat model

Background  

In the Western world, endometrial cancers are the most common gynaecological neoplastic disorders among women. Initial symptoms are often vague and may be confused with several other conditions or disorders. Thus, there is a need for an easy and reliable diagnostic tool. The objective of this work was to identify a gene expression signature specific for endometrial adenocarcinomas to be used for testing potential endometrial biomarkers.     

17beta-estradiol suppresses TLR3-induced cytokine and chemokine production in endometrial epithelial cells

Background  

The human endometrium is an important site for contact between the host and pathogens ascending the reproductive tract, and thus plays an important role in female reproductive tract immunity. Previous work in our laboratory has suggested that Toll-like receptors (TLRs) are involved in endometrial epithelial recognition of pathogens and that ligation of endometrial TLRs results in the production of cytokines and chemokines important for both immune and reproductive functions of the endometrium. We have also demonstrated cyclic regulation of TLR3 mRNA and protein expression in human endometrium, suggesting that steroid hormones might play a role in the expression and function of TLR3. In this study, the effects of 17beta-estradiol (E2) and progesterone (P) on TLR3 expression and function in endometrial cell lines were investigated.     

Effect of a povidone-iodine intrauterine infusion on progesterone levels and endometrial steroid receptor expression in mares

Background  

Intrauterine infusions have been widely used for the treatment of endometritis in the mare. Nevertheless, their consequences on endocrine and endometrial molecular aspects are unknown. We studied the effect of a 1% povidone-iodine solution intrauterine infusion on progesterone levels, endometrial histology and estrogen (ERα) and progesterone (PR) receptor distribution by immunohistochemistry.     

Potential action of androstenedione on the proliferation and apoptosis of stromal endometrial cells

Background

Hyperandrogenic conditions have been associated with a high prevalence of endometrial pathologies related to cell survival. However, the action of androgens on proliferation and apoptosis in endometrial cells is poorly understood. Therefore, the aim of the present study was to evaluate the effect of androstenedione on cell proliferation, cell death and expression of estrogen receptor (ER) isoforms and proteins related to apoptosis in endometrial cells using two in vitro experimental approaches.

Methods

The endometrial tissue was obtained from 20 eumenorrheic women [28.7 (25 – 35) years] during the early secretory phase. We analyzed cell proliferation (immunohistochemistry of Ki-67 and spectrophotometric assay); apoptosis (DNA fragmentation (TUNEL) and Annexin V-FITC binding); ER-alpha, ER-beta bcl-2 and bax mRNA abundance (RT-PCR) in explants and isolated endometrial epithelial (EEC) and stromal cells (ESC) incubated with androstenedione 1 micro mol/l (A4) or A4 plus hydroxyflutamide 10 micro mol/l (F) for 24 h.

Results

In explants, A4 induced an increase of cell proliferation and a decrease on apoptosis in the stromal compartment (p < 0.05). In isolated ESC, proliferation augmented with A4 (p < 0.05), whereas, no significant modifications in the expression of ER-alpha, ER-beta bcl-2 and bax nor in the apoptotic index were observed. In EEC, A4 increase the ER-beta mRNA abundance (p < 0.05) and a decrease of the bcl-2/bax ratio (p < 0.05), without an increase in the apoptotic index. Hydroxyflutamide reverted the effect of androstenedione on the parameters described.

Conclusions

These results indicate that androstenedione may modulate cell survival, expression of ER-beta and proteins related to apoptosis, suggesting a potential mechanism that associates the effect of hyperandrogenemia on the endometrial tissue.

     

Autophagy regulated by lncRNA HOTAIR contributes to the cisplatin-induced resistance in endometrial cancer cells

Objectives

To identify whether lncRNAs (long non-coding RNA) participate in the regulation of cisplatin-resistant induced autophagy in endometrial cancer cells.

Results

Autophagy activity was significantly boosted in cisplatin-resistant Ishikawa cells, a human endometrial cancer cell line, compared with that in parental Ishikawa cells. After analyzing the overall long noncoding RNA (lncRNA) profiling, a meaningful lncRNA, HOTAIR, was identified. It was down-regulated simultaneously in cisplatin-resistant Ishikawa cells and parental Ishikawa cells treated with cisplatin. RNA interference of HOTAIR reduced the proliferation of cisplatin-resistant Ishikawa cells and enhanced the autophagy activity of cisplatin-resistant Ishikawa cells with or without cisplatin treatment, in addition, beclin-1, multidrug resistance (MDR), and P-glycoprotein (P-gp) were mediated by lncRNA HOTAIR.

Conclusions

It is clear that lncRNAs, specifically HOTAIR, can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by influencing Beclin-1, MDR, and P-gp expression.

     

Quantity and quality of retrograde menstruation: a case control study

Background  

The purpose of this study was to test the hypothesis that menstruation is associated with a higher concentration of endometrial cells in peritoneal fluid(PF) and with increased white and red blood cell concentration in PF when compared to nonmenstrual phases of the cycle.     

The associated factors to endometrial cavity fluid and the relevant impact on the IVF-ET outcome

Background  

Endometrial cavity fluid (ECF) is a fluid accumulation within the endometrial cavity. The significance of ECF remains unclear during the program of in vitro fertilization-embryo transfer (IVF-ET). The aim of the present study was to investigate the associated factors to ECF, visualized through ultrasound at the day of oocyte retrieval, and the relevant impact on the outcome of IVF-ET.     

Human endometrial CD98 is essential for blastocyst adhesion

Background

Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans.

Methods and Principal Findings

Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate.

Conclusions

These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window.     

Combined analysis of endometrial thickness and pattern in predicting outcome of in vitro fertilization and embryo transfer: a retrospective cohort study

Objective  

To evaluate the combined effect of endometrial thickness and pattern on clinical outcome in patients undergoing in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET).     

An inhibitor of K+ channels modulates human endometrial tumor-initiating cells

Background

Many potassium ion (K⁺) channels function as oncogenes to sustain growth of solid tumors, but their role in cancer progression is not well understood. Emerging evidence suggests that the early progenitor cancer cell subpopulation, termed tumor initiating cells (TIC), are critical to cancer progression.

Results

A non-selective antagonist of multiple types of K⁺ channels, tetraethylammonium (TEA), was found to suppress colony formation in endometrial cancer cells via inhibition of putative TIC. The data also indicated that withdrawal of TEA results in a significant enhancement of tumorigenesis. When the TIC-enriched subpopulation was isolated from the endometrial cancer cells, TEA was also found to inhibit growth in vitro.

Conclusions

These studies suggest that the activity of potassium channels significantly contributes to the progression of endometrial tumors, and the antagonists of potassium channels are candidate anti-cancer drugs to specifically target tumor initiating cells in endometrial cancer therapy.     

Involvement of cyclin B1 in progesterone-mediated cell growth inhibition, G2/M cell cycle arrest, and apoptosis in human endometrial cell

Background  

Progesterone plays an important role in the proliferation and differentiation of human endometrial cells (hECs). Large-dose treatment with progesterone has been used for treatment of endometrial proliferative disorders. However, the mechanisms behind remain unknown.     

MicroRNA array and microarray evaluation of endometrial receptivity in patients with high serum progesterone levels on the day of hCG administration

Background  

To determine the effect of higher progesterone (P) level on endometrial receptivity.     

Prognostic significance of miR-205 in endometrial cancer

Purpose

microRNAs have emerged as key regulators of gene expression, and their altered expression has been associated with tumorigenesis and tumor progression. Thus, microRNAs have potential as both cancer biomarkers and/or potential novel therapeutic targets. Although accumulating evidence suggests the role of aberrant microRNA expression in endometrial carcinogenesis, there are still limited data available about the prognostic significance of microRNAs in endometrial cancer. The goal of this study is to investigate the prognostic value of selected key microRNAs in endometrial cancer by the analysis of archival formalin-fixed paraffin-embedded tissues.

Experimental Design

Total RNAs were extracted from 48 paired normal and endometrial tumor specimens using Trizol based approach. The expression of miR-26a, let-7g, miR-21, miR-181b, miR-200c, miR-192, miR-215, miR-200c, and miR-205 were quantified by real time qRT-PCR expression analysis. Targets of the differentially expressed miRNAs were quantified using immunohistochemistry. Statistical analysis was performed by GraphPad Prism 5.0.

Results

The expression levels of miR-200c (P<0.0001) and miR-205 (P<0.0001) were significantly increased in endometrial tumors compared to normal tissues. Kaplan-Meier survival analysis revealed that high levels of miR-205 expression were associated with poor patient overall survival (hazard ratio, 0.377; Logrank test, P = 0.028). Furthermore, decreased expression of a miR-205 target PTEN was detected in endometrial cancer tissues compared to normal tissues.

Conclusion

miR-205 holds a unique potential as a prognostic biomarker in endometrial cancer.     

The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome

Background  

To evaluate the relationship between endometrial thickness on day of human chorionic gonadotrophin administration (hCG) and pregnancy outcome in a large number of consecutive in vitro fertilization and embryo transfer (IVF-ET) cycles.