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

Miyata, Hiroshi; Mori, Taisuke; Ito, Fumihiko; Yamamoto, Takuro; Akiyama, Makoto; Kokabu, Tetsuya; Yoriki, Kaori; Umemura, Satoshi; Akashi, Koichi; Kitawaki, Jo

doi:10.18632/oncotarget.9151

Cited by 35 publications

(31 citation statements)

References 46 publications

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“…[ 15 ] Two mammalian ERs have been identified, ERα and ERβ. [ 16 ] Previous studies revealed that estrogen represses SOST expression through ERβ. [ 17 ] To investigate if the differential gene expression in the E2-treated MC3T3-E1cells was mediated through ERβ, we analyzed the Bmpr1a and Tgfbr1 promoters using online bioinformatics software ( http://jaspar.binf.ku.dk/ ).…”

Section: R Esultsmentioning

confidence: 99%

Estrogen-induced Tgfbr1 and Bmpr1a Expression Repressed via Estrogen Receptor Beta in MC3T3-E1 Cells

He¹,

Liu²,

Li³

et al. 2018

Chinese Medical Journal

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Background:Estrogen, as an important hormone in human physiological process, is closely related to bone metabolism. The aim of this study was to investigate the mechanism of estrogen on osteoblasts metabolism in MC3T3-E1 cells.Methods:We treated the MC3T3-E1 cells with different concentrations of β-estradiol (0.01, 0.1, 1, and 10 nmol/L), observed the morphological changes of the cells, and detected the cell's proliferation and apoptosis of MC3T3-E1 cells. Two transcriptome libraries were constructed and sequenced. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the differentially expressed genes (DEGs), and then treated the MC3T3-E1 cells with estrogen receptor (ER) inhibitors α and β, respectively, and then examined the expression of Tgfbr1 and Bmpr1a genes. The promoter of Tgfbr1 and Bmpr1a gene was analyzed, and the ER response elements were identified. Finally, ChIP was used to verify the binding of ER to Tgfbr1 and Bmpr1a promoter.Results:In the high-concentration β-estradiol treatment group (1 nmol/L and 10 nmol/L), there was no significant difference in the morphology of the cells under the microscope, 1 nmol/L and 10 nmol/L treated group appeared statistically significant difference in cell apoptosis and proliferation (P < 0.05 and P < 0.01, respectively). We found 460 DEGs compared with the control group. Among the DEGs, there were 66 upregulated genes and 394 downregulated genes. Gene ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that many bone metabolism-related biological processes and cell signaling pathways were disordered. The qRT-PCR verification showed that the expressions of Tgfbr1- and Bmpr1a-related genes in bone metabolism pathway in the 10 nmol/L treatment group were significantly decreased (P < 0.05). ER β was involved in the inhibitory effect of Tgfbr1 and Bmpr1a genes. The bioinformatics of the promoter found that there were three ER response elements in the promoter of Tgfbr1, and there were two ER response elements in Bmpr1a promoter regions. ChIP experiments showed that estrogen could enhance the binding of ERs to Tgfbr1 and Bmpr1a genes.Conclusions:Estrogen can promote the apoptosis and proliferation of osteoblasts simultaneously, and the mechanism may be the joint action of transforming growth factor-beta, Wnt, mitogen-activated protein kinase, and nuclear factor-kappaB bone metabolism-related signaling pathway. Estrogen inhibits the expression of Tgfbr1 and Bmpr1a genes through ER β and affects the metabolism of MC3T3-E1 osteoblasts.

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Section: R Esultsmentioning

confidence: 99%

Estrogen-induced Tgfbr1 and Bmpr1a Expression Repressed via Estrogen Receptor Beta in MC3T3-E1 Cells

He¹,

Liu²,

Li³

et al. 2018

Chinese Medical Journal

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“…Th e changes in these genes expression in cells without IRE1 signaling enzyme function possible contribute in the suppression of glioma cell proliferation and tumor growth, because there are data indicating that the estrogen receptor related factors play an important role in the control of cell proliferation and apoptosis (Cho et al 2010;Lapierre et al 2015;Tiwari et al 2015). It is possible that increased expression of FAM162A, PGRMC2, TRIM16 and SLC39A6 genes as well as decreased expression of ESRRA, and NRIP1 genes (Figure 1) may contribute to the suppression of the proliferation and glioma growth from glioma cells with IRE1 knockdown (Auf et al 2010(Auf et al , 2013Aziz et al 2015;Casaburi et al 2015;Minchenko et al 2015;Zhang et al 2015;Matsushima et al 2016). Th erefore, suppressing of NRIP1, which modulates transcriptional activity of the estrogen receptor, as well as knockdown of a site-specifi c transcription regulator ESRRA/NR3B1 inhibits growth of the cancer cells in vitro and in vivo (Aziz et al 2015;Matsushima et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that increased expression of FAM162A, PGRMC2, TRIM16 and SLC39A6 genes as well as decreased expression of ESRRA, and NRIP1 genes (Figure 1) may contribute to the suppression of the proliferation and glioma growth from glioma cells with IRE1 knockdown (Auf et al 2010(Auf et al , 2013Aziz et al 2015;Casaburi et al 2015;Minchenko et al 2015;Zhang et al 2015;Matsushima et al 2016). Th erefore, suppressing of NRIP1, which modulates transcriptional activity of the estrogen receptor, as well as knockdown of a site-specifi c transcription regulator ESRRA/NR3B1 inhibits growth of the cancer cells in vitro and in vivo (Aziz et al 2015;Matsushima et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…ESRRA is widely expressed in a range of tissues and accumulating evidence has supported that the high expression of ERRα correlates with poor prognosis of various human malignancies. However, knockdown of NR3B1 has antitumor eff ect (Casaburi et al 2015;Zhang et al 2015;Matsushima et al 2016). It has been reported that mitochondrial biogenesis is required for the anchorageindependent survival and propagation of stem-like cancer cells and regulated by various transcription factors including ESRRA Wada and Nakatsuka 2016).…”

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confidence: 99%

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Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

et al. 2017

Endocrine Regulations

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Objective. Th e aim of the present study was to examine the eff ect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoded estrogen related proteins (NRIP1/RIP140, TRIM16/EBBP, ESRRA/NR3B1, FAM162A/E2IG5, PGRMC2/PMBP, and SLC39A6/LIV-1) and their hypoxic regulation in U87 glioma cells for evaluation of their possible signifi cance in the control of glioma cells proliferation.Methods. Th e expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by a quantitative polymerase chain reaction.Results. Inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 signaling enzyme function up-regulates the expression of EBBP, E2IG5, PGRMC2, and SLC39A6 genes is in U87 glioma cells in comparison with the control glioma cells, with more signifi cant changes for E2IG5 and PGRMC2 genes. At the same time, the expression of NRIP1 and ESRRA genes is strongly down-regulated in glioma cells upon inhibition of IRE1. We also showed that hypoxia increases the expression of E2IG5, PGRMC2, and EBBP genes and decreases NRIP1 and ESRRA genes expression in control glioma cells. Furthermore, the inhibition of IRE1 in U87 glioma cells decreases the eff ect of hypoxia on the expression of E2IG5 and PGRMC2 genes, eliminates hypoxic regulation of NRIP1 gene, and enhances the sensitivity of ESRRA gene to hypoxic condition. Furthermore, the expression of SLC39A6 gene is resistant to hypoxia in both the glioma cells with and without IRE1 signaling enzyme function. Conclusions.Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function aff ects the expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells in gene specifi c manner and these changes possibly contribute to the suppression of the cell proliferation. Most of these genes are regulated by hypoxia and preferentially through IRE1 signaling pathway of endoplasmic reticulum stress.

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“…24 In endometrial cancer, increased expression of ERRa has been associated with advanced clinical stage and aggressive histology and ERRa silencing resulted in reduced cell proliferation in vitro. 25 All these data imply that dysregulation of ERRs may be active in various gynecological disease conditions.…”

Section: Fig 2 Examples Of Erra Immunostainingmentioning

confidence: 97%

Expression of Estrogen-Related Receptors in Localized Provoked Vulvodynia

Aalto

Huotari-Orava

Luhtala³

et al. 2020

BioResearch Open Access

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Eight percent of women suffer from vulvodynia, a chronic pain condition with unknown etiology. Inflammation and dysregulation of estrogen signaling have been suggested to play a role in the pathogenesis of localized provoked vulvodynia (LPV). Therefore, the aim of the study was to analyze protein expression levels of estrogenrelated receptors ERRa, ERRß, ERRc, estrogen receptor (ERa), and progesterone receptor (PRa) and CD3-positive T cells in the vulvar vestibulum obtained from women suffering from LPV in comparison to healthy, unaffected controls. Vulvar vestibulum tissue specimens were obtained from LPV patients (n = 12) who had undergone modified posterior vestibulectomy and from 15 healthy controls. Protein expression of ERRa, ERRß, ERRc, ERa, and PRa and CD3-positive T cells was analyzed by immunohistochemistry (IHC). Expression of ERRß was significantly more pronounced in samples from LPV compared to healthy controls (p = 0.006). No significant difference in the expression patterns of ERRa, ERRc, ERa, PRa, or CD3 cells was detected. To our knowledge, this is the first study reporting ERR expression in normal vestibulum and in vestibulectomy samples from LPV patients. The higher level of ERRß expression detected by IHC may reflect dysregulation of estrogen signaling in LPV.

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

Cited by 35 publications

References 46 publications

Estrogen-induced Tgfbr1 and Bmpr1a Expression Repressed via Estrogen Receptor Beta in MC3T3-E1 Cells

Estrogen-induced Tgfbr1 and Bmpr1a Expression Repressed via Estrogen Receptor Beta in MC3T3-E1 Cells

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

Expression of Estrogen-Related Receptors in Localized Provoked Vulvodynia

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