Secreted frizzled-related protein 2 (SFRP2) expression promotes lesion proliferation via canonical WNT signaling and indicates lesion borders in extraovarian endometriosis

Heinosalo, Taija; Gabriel, Michael; Kallio, Lauri; Adhikari, Prem Raj; Huhtinen, Kaisa; Laajala, Teemu D.; Kaikkonen, Elina; Mehmood, Arfa; Suvitie, Pia; Kujari, Harry; Aittokallio, Tero; Perheentupa, Antti; Poutanen, Matti

doi:10.1093/humrep/dey026

Cited by 23 publications

(25 citation statements)

References 45 publications

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“…12 In addition, Tabib et al 13 show DPP4 expression in FBs of both dermal layers in human skin, and suggest a novel major FB population characterized by co-expression of DPP4 and secreted frizzled related protein 2 (SFRP2), a soluble modulator of Wnt signaling. 17,18 However, most of the relevant literature on the role of DPP4-expressing skin fibroblasts still originates from mouse studies. Rinkevich et al demonstrated that a distinct DPP4-expressing lineage of FBs in the mouse skin was responsible for elevated ECM deposition and fibrosis during scar formation.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

et al. 2020

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Though skin fibroblasts (FB) are the main cell population within the dermis, the different skin FB subsets are not well characterized and the traditional classification into reticular and papillary FBs has little functional relevance. To fill the gap of knowledge on FB diversity in human skin, we performed single‐cell RNA sequencing. Investigation of marker genes for the different skin cell subtypes revealed a heterogeneous picture of FBs. When mapping reticular and papillary FB markers, we could not detect cluster specificity, suggesting that these two populations show a higher transcriptional heterogeneity than expected. This finding was further confirmed by in situ hybridization, showing that DPP4 was expressed in both dermal layers. Our analysis identified six FB clusters with distinct transcriptional signatures. Importantly, we could demonstrate that in human skin DPP4+ FBs are the main producers of factors involved in extracellular matrix (ECM) assembly. In conclusion, we provide evidence that hitherto considered FB markers are not ideal to characterize skin FB subpopulations in single‐cell sequencing analyses. The identification of DPP4+ FBs as the main ECM‐producing cells in human skin will foster the development of anti‐fibrotic treatments for the skin and other organs.

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Section: Introductionmentioning

confidence: 99%

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

et al. 2020

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“…For example, CSCL12 may promote the proliferation, migration and invasion of endometriosis ( 30 ). In addition, CYP1B1 ( 31 ), ETS1 ( 32 ), IGF1 ( 33 ), NOS3 ( 34 ), SFRP2 ( 35 ) and SLIT3 ( 36 ), which were previously identified to serve important roles in endometriosis, were positively correlated with LINC01279.…”

Section: Discussionmentioning

confidence: 91%

Identification of LINC01279 as a cell cycle‑associated long non‑coding RNA in endometriosis with GBA analysis

et al. 2018

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Endometriosis affects 6–10% of women of reproductive age. Though a significant amount of research has explored the pathogenesis of endometriosis, little is clear. Elucidating the mechanisms is urgently required for improving the therapeutic efficiency of endometriosis treatment. Long non-coding RNAs (lncRNAs) have recently acquired extensive attention as regulatory components in a variety of biological processes and diseases. However, the functions of many lncRNAs in endometriosis are poorly understood. Therefore, the exploration of the dysregulated genes in endometriosis, particularly lncRNAs, is of importance. In the present study, datasets for endometriosis, including GSE7305, GSE7846, GSE29981 and E-MTAB-694, were downloaded from Gene Expression Omnibus and ArrayExpress. Then, the limma and Affy packages were used to analyze the CEL file. The RankProd method was used to conduct meta-analysis. Long intergenic non-protein coding RNA 1279 (LINC01279) was significantly upregulated in the three datasets, and was the most upregulated lncRNA as determined by the RankProd method. Gene set enrichment and Gene Ontology analyses were conducted, which revealed that LINC01279 is likely to function as a cell cycle mediator in endometriosis. Finally, it was identified that LINC01279 is strongly associated with certain previously identified key factors in the development of endometriosis, including cyclin-dependent kinase 14 and C-X-C motif chemokine ligand 12. Thus, it was demonstrated that LINC01279 may be associated with the pathogenesis of endometriosis. This may potentially represent a target in the therapy of endometriosis.

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“…In addition, mutations of multiple cancer-associated genes are linked to endometriosis, like oncogene of KRAS and antioncogenes of PTEN and TNF [8]. Nevertheless, the pathogenesis of endometriosis is still not well understood since a lack of targeted medical treatment [9].…”

Section: Introductionmentioning

confidence: 99%

“…The Wnt signaling pathway is one of the well-known key cascades that regulate stemness and development, and the function of the Wnt signaling pathway in oncogenesis is presented in many types of tumors [13]. A recent study has revealed that secreted frizzled-related protein 2 (SFRP2) regulates the growth of endometriosis lesions and indicates the borders of endometriosis lesions together with CTNNB1, functioning as a typical stimulant of Wnt/CTNNB1 signaling pathway in endometriosis [9]. Furthermore, the engraftment and survival of desquamated endometrium are critically dependent on angiogenesis, and the Wnt/β-catenin signaling pathway plays a significant role in driving neovascularization [14].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of AQP1 silencing on adhesion and angiogenesis in ectopic endometrial cells of mice with endometriosis through activating the Wnt signaling pathway

Shu

Gao

et al. 2019

Cell Cycle

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The development mechanism of endometriosis remains unknown. Water channel aquaporin-1 (AQP1) enhances water flux across cell membranes, which is highly expressed and associated with cell migration, metastasis and angiogenesis in some human cancers. In this study, the role of the Wnt signaling pathway mediated by AQP1 in endometriosis was investigated, in a bid to provide new therapeutic targets for endometriosis. Microarray expression profiles were screened to acquired differentially expressed genes related to endometriosis. Mouse models with endometriosis were established and grouped. The level of endometriosis was evaluated by measurement of the volume of ectopic region. The expression of AQP1, pathway-related factors (Wnt1 and Wnt4), adhesion molecules (VCAM-1 and ICAM-1), invasive factors (MMP-2, MMP-9, TIMP-1 and TIMP-2), angiogenic factors (VEGF-A, VEGFR1 and VEGFR2) and apoptotic factors (Caspase-3, Caspase-9, Bax and BcL-2) was measured by RT-qPCR and western blot analysis. Furthermore, the role of AQP1 in adhesion, invasion, angiogenesis, and apoptosis of ectopic endometrial cells was determined by transfection of si-AQP1 plasmid. AQP1 was robustly expressed in endometriosis. AQP1 gene silencing alleviated the progression of endometriosis by activating the Wnt signaling pathway in mice with endometriosis. Specifically, silencing of AQP1 gene inhibited ectopic endometrial cell adhesion and invasion abilities, suppressed angiogenesis while promoted apoptosis. Collectively, the present study highlights the role of AQP1 in the regulation of the Wnt signaling pathway in endometriosis mouse models, suggesting that AQP1 could represent a new target aimed at improving the survival of patients with endometriosis.

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Secreted frizzled-related protein 2 (SFRP2) expression promotes lesion proliferation via canonical WNT signaling and indicates lesion borders in extraovarian endometriosis

Abstract: This study was funded by the Academy of Finland and by Tekes: Finnish Funding Agency for Innovation. The authors have no conflict of interest to declare.

Cited by 23 publications

References 45 publications

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

Deciphering the functional heterogeneity of skin fibroblasts using single‐cell RNA sequencing

Identification of LINC01279 as a cell cycle‑associated long non‑coding RNA in endometriosis with GBA analysis

Inhibitory effect of AQP1 silencing on adhesion and angiogenesis in ectopic endometrial cells of mice with endometriosis through activating the Wnt signaling pathway

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