Dataset Information

Reduced alternative splicing of estrogen receptor alpha in the endometrium of women with endometriosis.

ABSTRACT: Endometriosis is a condition which involves the presence of uterine stroma and glands outside of the uterine cavity and represents one of the most prevalent disorders of the female reproductive tract. The key symptom of endometriosis is pain, including dysmenorrhea, deep dyspareunia, and chronic pelvic pain. As such, endometriosis has significant economic consequences within the healthcare system and can influence the daily quality of life in affected patients. However, the pathophysiology of this disease and the mechanisms in which this condition generates pain are very unclear. This study, involving 30 women with endometriosis and 28 controls without endometriosis, aimed to investigate relative levels of estrogen receptor alpha (ER?) splice variants in the endometrium of women with and without endometriosis and investigate potential links to the severity of pain. Wild type (wt)-ER? was dominantly expressed in human endometrium while the expression of ER?-del.4, ER?-del.7, and ER?-del.3,4 was significantly reduced in endometriosis patients compared with healthy patients (p < 0.05). Furthermore, the relative ratios of wtER?:ER?-del.4, and wtER?:ER?-del.3,4 were associated with the severity of pain in endometriosis patients (p < 0.05). Consequently, analyzing differences in the relative levels of four types of ER? splice variant in the endometrium of patients with endometriosis may help in the development of endometriosis-targeted treatment and the development of appropriate therapies.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5746374 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Reduced alternative splicing of estrogen receptor alpha in the endometrium of women with endometriosis.

Zhang Ying Y Zhang Yong Y Zhao Chunbo C Yu Tiantian T Liu Ye Y Shi Weihui W Shi Fengtao F Liu Xinmei X Sheng Jianzhong J Huang Hefeng H Xu Hong H

Oncotarget 20171127 66

Endometriosis is a condition which involves the presence of uterine stroma and glands outside of the uterine cavity and represents one of the most prevalent disorders of the female reproductive tract. The key symptom of endometriosis is pain, including dysmenorrhea, deep dyspareunia, and chronic pelvic pain. As such, endometriosis has significant economic consequences within the healthcare system and can influence the daily quality of life in affected patients. However, the pathophysiology of th ...[more]

PMID: 29299139

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Project description:BackgroundAlternative splicing is critical for generating complex proteomes in response to extracellular signals. Nuclear receptors including estrogen receptor alpha (ER?) and their ligands promote alternative splicing. The endogenous targets of ER?:estradiol (E2)-mediated alternative splicing and the influence of extracellular kinases that phosphorylate ER? on E2-induced splicing are unknown.MethodsMCF-7 and its anti-estrogen derivatives were used for the majority of the assays. CD44 mini gene was used to measure the effect of E2 and AKT on alternative splicing. ExonHit array analysis was performed to identify E2 and AKT-regulated endogenous alternatively spliced apoptosis-related genes. Quantitative reverse transcription polymerase chain reaction was performed to verify alternative splicing. ER? binding to alternatively spliced genes was verified by chromatin immunoprecipitation assay. Bromodeoxyuridine incorporation-ELISA and Annexin V labeling assays were done to measure cell proliferation and apoptosis, respectively.ResultsWe identified the targets of E2-induced alternative splicing and deconstructed some of the mechanisms surrounding E2-induced splicing by combining splice array with ER? cistrome and gene expression array. E2-induced alternatively spliced genes fall into at least two subgroups: coupled to E2-regulated transcription and ER? binding to the gene without an effect on rate of transcription. Further, AKT, which phosphorylates both ER? and splicing factors, influenced ER?:E2 dependent splicing in a gene-specific manner. Genes that are alternatively spliced include FAS/CD95, FGFR2, and AXIN-1. E2 increased the expression of FGFR2 C1 isoform but reduced C3 isoform at mRNA level. E2-induced alternative splicing of FAS and FGFR2 in MCF-7 cells correlated with resistance to FAS activation-induced apoptosis and response to keratinocyte growth factor (KGF), respectively. Resistance of MCF-7 breast cancer cells to the anti-estrogen tamoxifen was associated with ER?-dependent overexpression of FGFR2, whereas resistance to fulvestrant was associated with ER?-dependent isoform switching, which correlated with altered response to KGF.ConclusionE2 may partly alter cellular proteome through alternative splicing uncoupled to its effects on transcription initiation and aberration in E2-induced alternative splicing events may influence response to anti-estrogens.

Project description:BackgroundEstrogens play an important role in breast cancer (BC) development and progression; when the two isoforms of the estrogen receptor (ERα and ERβ) are co-expressed each of them mediate specific effects of these hormones in BC cells. ERβ has been suggested to exert an antagonist role toward the oncogenic activities of ERα, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ERβ in cancer cells. We have previously described the ERβ and ERα interactomes from BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ERα and ERβ pathways. Guided by these findings, here we performed RNA sequencing to investigate in depth the differences in the early transcriptional events and RNA splicing patterns induced by estradiol in cells expressing ERα alone or ERα and ERβ.ResultsExon skipping was the most abundant splicing event in the post-transcriptional regulation by estradiol. We identified several splicing events induced by ERα alone and by ERα+ERβ, demonstrating for the first time that ERβ significantly affects estrogen-induced splicing in BC cells, as revealed by modification of a subset of ERα-dependent splicing by ERβ, as well as by the presence of splicing isoforms only in ERβ+cells. In particular, we observed that ERβ+BC cell lines exhibited around 2-fold more splicing events than the ERβ- cells. Interestingly, we identified putative direct targets of ERβ-mediated alternative splicing by correlating the genomic locations of ERβ and ERα binding sites with estradiol-induced differential splicing in the corresponding genes.ConclusionsTaken together, these results demonstrate that ERβ significantly affects estrogen-induced early transcription and mRNA splicing in hormone-responsive BC cells, providing novel information on the biological role of ERβ in these tumors.

Dataset Information

Reduced alternative splicing of estrogen receptor alpha in the endometrium of women with endometriosis.

Publications

Reduced alternative splicing of estrogen receptor alpha in the endometrium of women with endometriosis.

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