Endometriosis Is Associated with a Significant Increase in hTERC and Altered Telomere/Telomerase Associated Genes in the Eutopic Endometrium, an Ex-Vivo and In Silico Study

Telomeres protect chromosomal ends and they are maintained by the specialised enzyme, telomerase. Endometriosis is a common gynaecological disease and high telomerase activity and higher hTERT levels associated with longer endometrial telomere lengths are characteristics of eutopic secretory endometrial aberrations of women with endometriosis. Our ex-vivo study examined the levels of hTERC and DKC1 RNA and dyskerin protein levels in the endometrium from healthy women and those with endometriosis (n = 117). The in silico study examined endometriosis-specific telomere- and telomerase-associated gene (TTAG) transcriptional aberrations of secretory phase eutopic endometrium utilising publicly available microarray datasets. Eutopic secretory endometrial hTERC levels were significantly increased in women with endometriosis compared to healthy endometrium, yet dyskerin mRNA and protein levels were unperturbed. Our in silico study identified 10 TTAGs (CDKN2A, PML, ZNHIT2, UBE3A, MCCC2, HSPC159, FGFR2, PIK3C2A, RALGAPA1, and HNRNPA2B1) to be altered in mid-secretory endometrium of women with endometriosis. High levels of hTERC and the identified other TTAGs might be part of the established alteration in the eutopic endometrial telomerase biology in women with endometriosis in the secretory phase of the endometrium and our data informs future research to unravel the fundamental involvement of telomerase in the pathogenesis of endometriosis.

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The effect of stretching on transmural shear wave anisotropy in cardiac shear wave elastography: An ex vivo and in silico study

2017 IEEE International Ultrasonics Symposium (IUS) ◽

10.1109/ultsym.2017.8091930 ◽

2017 ◽

Cited By ~ 1

Author(s):

Annette Caenen ◽

Abdullah Thabit ◽

Mathieu Pernot ◽

Darya Shcherbakova ◽

Luc Mertens ◽

...

Keyword(s):

Shear Wave ◽

In Silico ◽

Ex Vivo ◽

Shear Wave Elastography ◽

In Silico Study

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FKBP4 is regulated by HOXA10 during decidualization and in endometriosis

Reproduction ◽

10.1530/rep-11-0438 ◽

2012 ◽

Vol 143 (4) ◽

pp. 531-538 ◽

Cited By ~ 33

Author(s):

Huan Yang ◽

Yuping Zhou ◽

Benjiamin Edelshain ◽

Frederick Schatz ◽

Charles J Lockwood ◽

...

Keyword(s):

Menstrual Cycle ◽

Stromal Cells ◽

Secretory Phase ◽

Endometrial Stromal Cells ◽

Eutopic Endometrium ◽

Protein Levels ◽

Proliferative Phase ◽

Progestin Receptor ◽

Fertile Women

FKBP4 (FKBP52) and FKBP5 (FKBP51) are progestin receptor (PR) co-chaperone proteins that enhance and inhibit, respectively, progestin-mediated transcription by PR. Here, we examinedFKBP4andFKBP5expression in the eutopic endometrium of fertile women with endometriosis and effects of FKBP4 and FKBP5 on the decidualization of human endometrial stromal cells (HESCs), and assessed HOXA10 regulation of FKBP4. Expression ofFKBP4mRNA was increased in the late proliferative phase and remained elevated throughout the secretory phase.FKBP5expression was low and remained constant throughout the menstrual cycle. Compared with controls,FKBP4mRNA expression was decreased in the endometrium of women with endometriosis, whereas no significant endometriosis-related change was seen forFKBP5. Cultured HESCs were treated with eitherFKBP4orFKBP5siRNA and then decidualized by incubation with progesterone (P4) and 8-bromoadenosine cAMP. Treatment of HESCs withFKBP4siRNA resulted in 60% lowerIGFBP1expression. In contrast, incubation withFKBP5siRNA did not significantly decreaseIGFBP1expression duringin vitrodecidualization.HOXA10andFKBP4expression increased in parallel duringin vitrodecidualization. In HESCs, overexpressed HOXA10 enhanced FKBP4 mRNA and protein levels, whereas HOXA10 knockdown decreased FKBP4 mRNA and protein levels compared with controls. Similarly, duringin vitrodecidualization,FKBP4expression was decreased in HOXA10-silenced cells. EnhancedHOXA10expression in HESCs elicits a decidualization mediating increase inFKBP4expression. The findings are consistent with the observation that women with endometriosis have diminishedFKBP4expression leading to impaired decidualization and infertility. The P4resistance seen in endometriosis may be mediated through HOXA10-regulatedFKBP4expression.

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Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Methods and Protocols ◽

10.3390/mps3030063 ◽

2020 ◽

Vol 3 (3) ◽

pp. 63 ◽

Cited By ~ 1

Author(s):

Alice Bradfield ◽

Lucy Button ◽

Josephine Drury ◽

Daniel C. Green ◽

Christopher J. Hill ◽

...

Keyword(s):

Endometrial Cancer ◽

In Silico ◽

Prognostic Markers ◽

Treatment Strategies ◽

Interaction Network ◽

Telomerase Activity ◽

Telomere Maintenance ◽

The Cancer Genome Atlas ◽

Future Research

Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.

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An assessment of the multifactorial profile of steroid-metabolizing enzymes and steroid receptors in the eutopic endometrium during moderate to severe ovarian endometriosis

Reproductive Biology and Endocrinology ◽

10.1186/s12958-019-0553-0 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

G. Anupa ◽

Jai Bhagwan Sharma ◽

Kallol K. Roy ◽

Jayasree Sengupta ◽

Debabrata Ghosh

Keyword(s):

Menstrual Cycle ◽

Steroid Receptors ◽

Expression Profiles ◽

Proof Of Concept ◽

Secretory Phase ◽

Tissue Concentrations ◽

Ovarian Endometriosis ◽

Metabolizing Enzymes ◽

Eutopic Endometrium ◽

Protein Levels

Abstract Background Previous studies of expression profiles of major endometrial effectors of steroid physiology in endometriosis have yielded markedly conflicting conclusions, presumably because the relative effects of type of endometriosis, fertility history and menstrual cycle phases on the measured variables were not considered. In the present study, endometrial mRNA and protein levels of several effectors of steroid biosynthesis and action in patients with stage III-IV ovarian endometriosis (OE) with known fertility and menstrual cycle histories were compared with the levels in control endometrium to test this concept. Methods Endometrial samples were collected from patients without endometriosis (n = 32) or OE stages III-IV (n = 52) with known fertility and cycle histories. qRT-PCR and immunoblotting experiments were performed to measure levels of NR5A1, STAR, CYP19A1, HSD17Bs, ESRs and PGR transcripts and proteins, respectively. Tissue concentrations of steroids (P4, T, E1 and E2) were measured using ELISAs. Results The levels of expression of aromatase and ERβ were lower (P < 0.0001) and 17β-HSD1 (P < 0.0001) and PRA (P < 0.01) were higher in OE endometrium. Lower aromatase levels and higher 17β-HSD1 levels were detected in fertile (aromatase: P < 0.05; 17β-HSD1: P < 0.0001) and infertile (aromatase: P < 0.0001; 17β-HSD1: P < 0.0001) OE endometrium than in the matched control tissues. Both proliferative (PP) and secretory (SP) phase OE samples expressed aromatase (P < 0.0001) and ERβ (PP: P < 0.001; SP: P < 0.01) at lower levels and 17β-HSD1 (P < 0.0001) and PRA (PP: P < 0.01; SP: P < 0.0001) at higher levels than matched controls. Higher 17β-HSD1 (P < 0.01) and E2 (P < 0.05) levels and a lower (P < 0.01) PRB/PRA ratio was observed in infertile secretory phase OE endometrium than in control. Conclusions We report that dysregulated expression of 17β-HSD1 and PGR resulting in hyperestrogenism and progesterone resistance during the secretory phase of the menstrual cycle, rather than an anomaly in aromatase expression, was the hallmark of eutopic endometrium from infertile OE patients. Furthermore, the results provide proof of concept that the fertility and menstrual cycle histories exerted relatively different effects on steroid physiology in the endometrium from OE patients compared with the control subjects.

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