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Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer.

ABSTRACT: Estrogen-related receptor (ERR)? presents structural similarities with estrogen receptor (ER)?. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERR? in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERR? was expressed in all examined tissues and the elevated expression levels of ERR? were associated with advanced clinical stages and serous histological type (p < 0.01 for each). ERR? knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro (p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERR? knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERR? knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERR? knockdown xenografts (p < 0.01). These findings indicate that ERR? may serve as a novel molecular target for the treatment of endometrial cancer.

SUBMITTER: Matsushima H

PROVIDER: S-EPMC5085142 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer.

Matsushima Hiroshi H Mori Taisuke T Ito Fumitake F Yamamoto Takuro T Akiyama Makoto M Kokabu Tetsuya T Yoriki Kaori K Umemura Shiori S Akashi Kyoko K Kitawaki Jo J

Oncotarget 20160601 23

Estrogen-related receptor (ERR)α presents structural similarities with estrogen receptor (ER)α. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and s ...[more]

PMID: 27153547

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Project description:PurposeTo explore the targeted therapy of estrogen-related receptor α (ERRα) in endometrial cancer (EC) cells and its potential mechanisms.MethodsThe mRNA and protein expression levels of ERRα and estrogen receptor α (ERα) were detected by qPCR and Western blotting in RL-952, AN3-CA, HEC-1A, and HEC-1B EC cell lines. After treatment with the ERRα-specific antagonist XCT790 or infection with lentivirus-mediated small interfering RNA (siRNA) targeting the ERRα (siRNA-ERRα), cell proliferation and apoptosis were evaluated by MTS assay and flow cytometry. After treatment with siRNA-ERRα, the expression profiles of transcription factors (TFs) were analyzed by protein/DNA arrays in EC cells.ResultsThe relative mRNA levels of ERRa in RL-952 (1±0.0831) and AN3-CA (1.162±0.0325) were significantly higher than those in HEC-1A (0.3081±0.0339) and HEC-1B (0.1119±0.0091) (P<0.05), and similar results were observed for ERRα protein levels. A higher ratio of ERa/ERRa was observed in ERα-positive RL-952 (10-fold) and ANC-3A (8.5-fold) cells, whereas a lower ratio was observed in ERα-negative HEC-1A (3.75-fold) and HEC-1B cells (0-fold). Both - exogenous XCT790 and endogenous siRNA-ERRα - can decrease the expression of ERRα, thereby inhibiting proliferation but promoting apoptosis in both ERα-positive and -negative EC cells. The XCT790 presented higher proliferation-inhibition and apoptosis rates in the ERα-positive than ERα-negative cells, whereas the siRNA-ERRα exhibited higher proliferation-inhibition and apoptosis rates in the ERα-negative than in ERα-positive cells. In total, 3 upregulated and 17 downregulated TFs were screened out by knocked-down expression of ERRα in all EC cells. Among them, the upregulated TFs organic cation transporter 3/4(Oct3/4), hepatic nuclear factor 4 (HNF4), HNF4 and chicken ovalbumin upstream TF (COUP-TF) as well as downregulated transcription factor EB (TFEB) were found to be statistically significant (P<0.05).ConclusionTargeting ERRα provides a promising novel endocrine therapeutic strategy.

Project description:BackgroundEstrogen receptor β (ERβ) has been repeatedly suggested to play important roles in hormone-dependent cancer like in tumors of the breast, ovary or prostate. In this study, we intended to further elucidate its role in endometrial cancer.MethodsFor this purpose, we knocked down ERβ expression in two endometrial cancer cell lines, the ERα-negative/ERβ-positive line HEC-1A and the ERα/β-positive cell line RL95/2, by means of siRNA transfection. Cell proliferation after transfection was assessed using the fluorescent CTB Assay (Promega). In order to elucidate possible molecular mechanisms which might underlie the effect on proliferation, we performed transcriptome analyses by means of human Affymetrix Human Gene Chip 2.0. Additionally, we treated the employed cell lines with different ERβ modulators to examine their effect on proliferation.ResultssiRNA-mediated knockdown of ERβ significantly increased proliferation of both endometrial cancer cell lines. In HEC-1A cells, proliferation was significantly increased 4, 5 and 6 days after transfection, with a maximum of about 1.7-fold (p < 0.05) on day 6. Endometrial RL95/2 cells with an ERβ knockdown exhibited a clearly enhanced proliferation on day 3 and days 4 to 8, when even 2.4-fold higher numbers of viable cells were detected (p < 0.01). Transcriptome analysis revealed that this was accompanied by increased expression of several genes being known to be upregulated in cancer, including proliferation-associated genes and oncogenes, and by repression of genes associated with differentiation, apoptosis or growth inhibition. Corroborating the observed knockdown effects, treatment with the ERβ antagonists PHTTP and (R, R) THC was also able to induce proliferation of both cell lines.ConclusionsOur data clearly support the putative role of ERβ as tumor suppressor in endometrium as previously suggested in studies on other tissues and encourage further studies to find out to what extent this molecule might be a potential therapy target in this cancer entity.

Project description:Estrogen and its metabolites play a critical role in the pathophysiology of the endometrium. The bioavailability of estrogen and estrogen metabolites in endometrial tissues depends on the expression of enzymes involved in estrogen biosynthesis and metabolism. Substantial evidence indicates that estrogen-dependent endometrial disorders are also associated with proinflammatory milieu. However, the mechanism whereby inflammation contributes to these conditions is not known.The objective of the study was to investigate the effect of TNF-alpha on estrogen metabolism and the expression of estrogen-metabolizing genes in human endometrial glandular epithelial cells (EM1).EM1 were treated with 17beta-estradiol (E2) with or without TNF-alpha. Capillary liquid chromatography-tandem mass spectrometry analysis was used for quantitative measurement of estrogens and estrogen metabolites. Western blot analysis, reporter gene assay, and real-time RT-PCR were used to assess the expression of estrogen-metabolizing genes.TNF-alpha treatment significantly increased the level of total estrogen and estrogen metabolites and significantly increased the rate of conversion of estrone (E1) into E2. TNF-alpha also enhanced the oxidative metabolism of estrogen into catecholestrogens with concomitant inhibition of their conversion into methoxyestrogens. Gene expression analysis revealed that TNF-alpha induced the expression of genes involved in E2 biosynthesis (steroidogenic factor-1 and aromatase) and activation (17beta- hydroxysteroid dehydrogenase type 1 and cytochrome P-450, 1B1) with simultaneous repression of genes involved in estrogen inactivation (17beta-hydroxysteroid dehydrogenase type 2; catechol O-methyltransferase; and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1).TNF-alpha increases the local estrogen biosynthesis in human endometrial glandular cells and directs estrogen metabolism into more hormonally active and carcinogenic metabolites. These effects may impact many physiological and pathological processes that occur within the endometrium.

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Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer.

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Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer.

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