A relational database to identify differentially expressed genes in the endometrium and endometriosis lesions

Gabriel, Michael; Fey, Vidal; Heinosalo, Taija; Adhikari, Prem Raj; Rytkönen, Kalle T.; Komulainen, Tuomo; Huhtinen, Kaisa; Laajala, Teemu D.; Siitari, Harri; Virkki, Arho; Suvitie, Pia; Kujari, Harry; Aittokallio, Tero; Perheentupa, Antti; Poutanen, Matti

doi:10.1038/s41597-020-00623-x

Cited by 44 publications

(33 citation statements)

References 40 publications

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“…To analyze the gene expression of our genes of interest in endometriotic tissue, the ENDOMET Turku Endometriosis Database [ 18 ] was used. We performed database analyses in up to 576 endometriotic samples of ectopic lesions of endometriosis patients and up to 82 healthy control samples.…”

Section: Resultsmentioning

confidence: 99%

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Impact of Musashi-1 and Musashi-2 Double Knockdown on Notch Signaling and the Pathogenesis of Endometriosis

Strauß

Greve

Gabriel

et al. 2022

IJMS

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The stem cell marker and RNA-binding protein Musashi-1 is overexpressed in endometriosis. Musashi-1-siRNA knockdown in Ishikawa cells altered the expression of stem cell related genes, such as OCT-4. To investigate the role of both human Musashi homologues (MSI-1 and MSI-2) in the pathogenesis of endometriosis, immortalized endometriotic 12-Z cells and primary endometriotic stroma cells were treated with Musashi-1- and Musashi-2-siRNA. Subsequently, the impact on cell proliferation, cell apoptosis, cell necrosis, spheroid formation, stem cell phenotype and the Notch signaling pathway was studied in vitro. Using the ENDOMET Turku Endometriosis database, the gene expression of stem cell markers and Notch signaling pathway constituents were analyzed according to localization of the endometriosis lesions. The database analysis demonstrated that expression of Musashi and Notch pathway-related genes are dysregulated in patients with endometriosis. Musashi-1/2-double-knockdown increased apoptosis and necrosis and reduced stem cell gene expression, cell proliferation, and the formation of spheroids. Musashi silencing increased the expression of the anti-proliferation mediator p21. Our findings suggest the therapeutic potential of targeting the Musashi–Notch axis. We conclude that the Musashi genes have an impact on Notch signaling and the pathogenesis of endometriosis through the downregulation of proliferation, stemness characteristics and the upregulation of apoptosis, necrosis and of the cell cycle regulator p21.

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Section: Resultsmentioning

confidence: 99%

“…Data Availability Statement: Patient gene expression datasets were retrieved and analyzed using the publicly accessible ENDOMET Turku Endometriosis Database (https://endometdb.utu.fi/, accessed on 15 December 2021) [18]. All experimental data presented in this study are contained in this manuscript.…”

Section: Discussionmentioning

confidence: 99%

Impact of Musashi-1 and Musashi-2 Double Knockdown on Notch Signaling and the Pathogenesis of Endometriosis

Strauß

Greve

Gabriel

et al. 2022

IJMS

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“…The expression levels of C3 and C3AR1 genes in control endometrium and various EM lesions (peritoneal, deep and ovarian EM) were analyzed using data extracted from the GEO (Gene Expression Omnibus of the National Center for Biotechnology Information-NCBI) with the series accession number GSE141549. Microarray analysis on samples obtained from 43 endometrium biopsies of healthy woman, 101 endometrium biopsies of EM patients and 190 EM lesions, and data normalization, have been described by Gabriel and colleagues ( 30 ).…”

Section: Methodsmentioning

confidence: 99%

The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

et al. 2021

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The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts.

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“…EndometDB incorporates the expression data from 115 endometriosis patients and 53 controls, with over 24,000 genes and clinical features. The mRNA expression of estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and CD68 in the endometrium and peritoneum of the control group, and in the eutopic and ectopic endometria and peritoneum of patients with endometriosis were analyzed in EndometDB (https://endometdb.utu.fi/gene_ analysis/) (19). Specifically, all clinical and sample data in the database were selected, and the patients were separated by age.…”

Section: Mrna Expression Of Estrogen Receptors and Cd68 Via Endometdbmentioning

confidence: 99%

A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68+ Macrophages

Wang

et al. 2021

Front. Immunol.

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Women with endometriosis may have a defective immune system. However, evidence of the immune responses of endometriosis patients with a history of endometriosis surgery is lacking, and the association between the location of endometriosis lesions and immune responses is unclear. This retrospective study included 117 females with reproductive failure and a history of endometriosis and 200 females with reproductive failure but without endometriosis to analyze their endometrial and peripheral immune responses. The results show that endometriosis was associated with decreased peripheral natural killer (NK) cytotoxicity and increased uterine macrophages. Peripheral NK cytotoxicity at effector-to-target ratios of 25:1 and 50:1 was significantly reduced in women with a history of endometriosis from that of the control group (26.6% versus 33.3% and 36.1% versus 43.3%, respectively, both P < 0.001). Furthermore, after further division of patients into three subgroups according to the location of endometriosis lesions, we observed that NK cytotoxicity in the endometriosis subgroups, especially the mixed endometriosis group, was strongly decreased from that of the controls (P = 0.001). The endometrial CD68+ macrophage proportion in the mixed endometriosis subgroup was higher than that in the control group (2.8% versus 2.1%, P = 0.043). In addition, the baseline estradiol (E2) level was weakly correlated with the percentage of endometrial macrophages (r = 0.251, P = 0.009), indicating a potential association among the endocrine system, endometrial immune environment, and endometriosis. This study indicated that peripheral NK cytotoxicity and endometrial immune cell profiles could be useful for diagnosing and treating endometriosis and endometriosis-related reproductive diseases.

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A relational database to identify differentially expressed genes in the endometrium and endometriosis lesions

Cited by 44 publications

References 40 publications

Impact of Musashi-1 and Musashi-2 Double Knockdown on Notch Signaling and the Pathogenesis of Endometriosis

Impact of Musashi-1 and Musashi-2 Double Knockdown on Notch Signaling and the Pathogenesis of Endometriosis

The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68+ Macrophages

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