Dataset Information

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers.

ABSTRACT: Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.

SUBMITTER: Rizner TL

PROVIDER: S-EPMC5474471 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers.

Rižner Tea Lanišnik TL Thalhammer Theresia T Özvegy-Laczka Csilla C

Frontiers in pharmacology 20170619

Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important ...[more]

PMID: 28674494

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Project description:STUDY QUESTION:How does aquaporin-3 (AQP3) affect endometrial receptivity? SUMMARY ANSWER:AQP3, which is regulated by the combination and estrogen (E2) and progesterone (P4), induces epithelial-mesenchymal transition (EMT) of endometrial epithelial cells. WHAT IS KNOWN ALREADY:Embryo implantation is an extremely complex process, and endometrial receptivity is essential for successful embryo implantation. Estrogen and progesterone regulate endometrial receptivity. AQP3, which is regulated by estrogen (E2), increases cell migration and invasion ability by regulating the expression of EMT-related factors and influencing the reorganization of the actin cytoskeleton. STUDY DESIGN, SIZE, DURATION:This study investigated the pathophysiological significance of AQP3 in human endometrial function during different phases of the menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS:AQP3 expression levels during different phases of the menstrual cycle were measured using immunohistochemical assays. In cells of different receptivity (high-receptive RL95-2 cells and low-receptive HEC-1A cells), the expression of AQP3 was measured using western blotting, qRT-PCR and immunofluorescence assays. Activities of AQP3, and its regulation by E2 and P4, were studied through in-vitro experiments using RL95-2 cells. MAIN RESULTS AND THE ROLE OF CHANCE:AQP3 expression in the mid- and late-secretory phases of the human endometrium is significantly higher than in other phases. Since AQP3 expression levels were higher in RL95-2 cells than in HEC-1A cells, mechanisms of AQP3 regulation by E2 and P4 were studied using RL95-2 cells. We provided the first report that P4 up-regulates AQP3 by directly targeting the promoter of the AQP3 gene. The up-regulation of AQP3 expression by a combination of E2 and P4 is significantly higher than that caused by either E2 or P4 alone. Together E2 and P4 promote RL95-2 cell migration and invasion by inducing EMT through AQP3. We also found that AQP3 co-localizes with ezrin and affects the formation of filopodia and lamellipodia during the E2 and P4-induced EMT process but has no effect on the expression of ezrin and F-actin. LARGE SCALE DATA:N/A. LIMITATIONS, REASONS FOR CAUTION:It is still unclear whether AQP3 is a main regulator of endometrial receptivity or one of several factors influencing the process. WIDER IMPLICATIONS OF THE FINDINGS:Further investigation on AQP3 may contribute to a greater understanding of endometrial receptivity. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the National Natural Scientific Grants of China (No. 31570798), the Program for Liaoning Excellent Talents in University (LR2017042), the Doctoral Scientific Research Foundation of Liaoning province (201601236), and the Liaoning Provincial Program for Top Discipline of Basic Medical Sciences. There are no conflicts of interest.

Project description:Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.

Dataset Information

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers.

Publications

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers.

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