Pharmacological blockage of the CXCR4-CXCL12 axis in endometriosis leads to contrasting effects in proliferation, migration, and invasion†

Ruiz, Abigail; Ruiz, Lynnette A.; Colón-Caraballo, Mariano; Torres-Collazo, Bryan J; Monteiro, Janice; Bayona, Manuel; Fazleabas, Asgerally T.; Flores, Idhaliz

doi:10.1093/biolre/iox152

Cited by 32 publications

(18 citation statements)

References 41 publications

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“…CXCL12 interacts with its specific receptor, C-X-C motif chemokine receptor 4 (CXCR4), which is not consistently over-expressed in these three datasets though. The CXCL12-CXCR4 axis promotes proliferation, migration, and invasion of endometriotic cells 44,45 . In human papillary thyroid carcinoma, the CXCL12-CXCR4 axis promotes EMT processes by activating the NF-κB signaling pathway 46 .…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis

Chen

Zhou

et al. 2020

Sci Rep

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Background: Endometriosis is a frequently occurring disease in women, which seriously affects their quality of life. However, its etiology and pathogenesis are still unclear. Methods: To identify key genes/ pathways involved in the pathogenesis of endometriosis, we recruited 3 raw microarray datasets (GSE11691, GSE7305, and GSE12768) from Gene Expression Omnibus database (GEO), which contain endometriosis tissues and normal endometrial tissues. We then performed in-depth bioinformatic analysis to determine differentially expressed genes (DEGs), followed by gene ontology (GO), Hallmark pathway enrichment and protein-protein interaction (PPI) network analysis. The findings were further validated by immunohistochemistry (IHC) staining in endometrial tissues from endometriosis or control patients. Results: We identified 186 DEGs, of which 118 were up-regulated and 68 were down-regulated. The most enriched DEGs in GO functional analysis were mainly associated with cell adhesion, inflammatory response, and extracellular exosome. We found that epithelial-mesenchymal transition (EMT) ranked first in the Hallmark pathway enrichment. EMT may potentially be induced by inflammatory cytokines such as CXCL12. IHC confirmed the down-regulation of E-cadherin (CDH1) and up-regulation of CXCL12 in endometriosis tissues. Conclusions: Utilizing bioinformatics and patient samples, we provide evidence of EMT in endometriosis. Elucidating the role of EMT will improve the understanding of the molecular mechanisms involved in the development of endometriosis. Endometriosis is a frequently occurring gynaecological disease characterised by chronic pelvic pain, dysmenorrhea and infertility 1. Its prevalence is estimated to be 10-15% of reproductive age females 2 and around to 20-48% in infertile women 3. Despite a number of theories being suggested to describe the molecular mechanisms underlying the development of endometriosis such as: Sampson's theory of retrograde menstruation 4 , ectopic implantation, epigenetic factors 5 , immune and inflammatory factors 6,7 , eutopic endometrial determinism 8 , and stem cell factors 9 ; disease pathogenesis is still not fully understood. At present, there have been several studies on the gene expression profiles of endometriosis 10-13 , which have identified various differentially expressed genes (DEGs) involved in the development of endometriosis. However, due to heterogeneity between each independent experiment as a result of variations in tissue or specimens and/ or different data processing methods, the identification of these DEGs is inconsistent. In this study, we integrated different studies using a non-biased approach, which may resolve these problems and enable the discovery of effective and reliable molecular markers. We downloaded 3 microarray datasets GSE11691 11 , GSE7305 12 , GSE12768 13 , from Gene Expression Omnibus database (GEO), which contain gene expression data from endometriosis tissues and normal endometrial tissues. We then performed deep bioinformatic analysis, including ident...

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Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis

Chen

Zhou

et al. 2020

Sci Rep

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“…In addition, chemokines are key players in the activation and are recruitment of immune cells at sites of inflammation. The CXCR4/CXCL12 axis is functional in endometriosis and plays a role in a number of diverse cellular functions, including immune surveillance, inflammation response, tissue homeostasis, and tumor growth and metastasis (106). CXCR4 expression is upregulated by vascular endothelial growth factor (VEGF), and plays an important role in the malignant transformation of endometriosis (107).…”

Section: Similar Epigenetic Modifications: Gene-environment Interactimentioning

confidence: 99%

Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis

et al. 2018

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In the present study, we summarize the role of the shared and independent (epi)genetic background between endometrioid carcinoma (EC) and clear cell carcinoma (CCC), two histological subtypes of endometriosis-associated ovarian cancer (EAOC). Using the PubMed database, we conducted a literature review of various studies related to the malignant transformation of endometriosis. Both endometriosis and EAOC face potential environmental hazards, including hemoglobin (Hb), heme and free iron, which induces DNA damage and mutations. Although EC is distinguished from CCC due to different morphologies, both represent common environmental profiles and maintain the similar (epi)genomic abnormalities with multiple overlaps and share similar molecular signatures. By contrast, EAOC also has diseasespecific gene signatures corresponding with each histological subtype: Estrogen receptor promotes EC cell proliferation ('go') and hepatocyte nuclear factor-1β (HNF-1β) induces CCC cell cycle arrest ('stop') under oxidative stress conditions. This model underscores a subtype-dependent 'go or stop' dichotomy, possibly through better ability to adapt in a changing environment. It was found that cyst fluid Hb and iron concentrations were significantly lower in EAOC when compared to benign ovarian endometrioma (OE), supporting the hypothesis that the redox imbalance plays a key role in the pathogenesis of EAOC. There are at least two phases of iron carcinogenesis and tumor progression: The initial wave of iron-induced oxidative stress and DNA mutations would be followed by the second big wave of subsequent synthesis of the antioxidants, which diminishes cellular oxidative stress capacity, increases apoptosis resistance and promotes tumor initiation and progression. Special emphasis is given to novel pathophysiological concepts of malignant transformation of endometriosis.

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“…Cell migration can be increased by the excessive expression of MMPs [37], leading to the local destruction of the extracellular matrix and the establishment of early lesions [38]. In fact, the levels of MMP-2 and MMP-9 were found to be higher in the peritoneal fluid of women with endometriosis compared to that of healthy patients [39,40]. Here, we have demonstrated that iron promotes the migration of human endometriotic cells and MMP-2 and MMP-9 expressions in human endometriotic cells.…”

Section: Discussionmentioning

confidence: 99%

Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype

Woo

Choi

2020

Biomedicines

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High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial–mesenchymal transition (EMT), but not growth, of 12Z human endometriotic cells. The expression of matrix metalloproteinase (MMP)-2/-9 was markedly increased through iron treatment in 12Z cells. Interestingly, intracellular reactive oxygen species (ROS) levels were significantly increased by iron in 12Z cells, and N-acetyl-L-cysteine significantly reduced iron-induced migration and MMP-2/-9 expression. Additionally, iron stimulated the activation of the NFκB pathway, and the activation was associated with iron-induced migration and MMP-2/-9 expression in 12Z cells. Moreover, iron markedly increased EMT and MMP-2/-9 expression in endometriotic lesions in an endometriosis mouse model. Taken together, these results suggest that iron may contribute to the migration abilities of human endometriotic cells via MMP expression through the ROS–NFκB pathway.

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Pharmacological blockage of the CXCR4-CXCL12 axis in endometriosis leads to contrasting effects in proliferation, migration, and invasion†

Cited by 32 publications

References 41 publications

Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis

Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis

Integrating modern approaches to pathogenetic concepts of malignant transformation of endometriosis

Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype

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