Available online 13 September 2022, 106296
Highlights•IGF2BP2, MEIS2, and GATA6 were all found to be overexpressed in ovarian endometriosis.
•MEIS2 and GATA6 were positively correlated with IGF2BP2.
•IGF2BP2 enhanced the mRNA stability of MEIS2 and GATA6.
•METTL3 and IGF2BP2 synergistically promoted the levels of MEIS2 and GATA6.
•Five small molecules with potential therapeutic effects for ovarian endometriosis were identified via the Connectivity Map Database.
AbstractBackgroundm6A-RNA modification mediated by the N6-methyladenosine RNA methylation-related molecule methyltransferase-like 3 has been implicated in the progression of endometriosis. However, the functions of other m6A regulators, especially in ovarian endometriosis, remain unknown.
MethodsThree datasets (GSE7305, GSE7307, and GSE37837) with diagnosed ovarian endometriosis were extracted from the Gene Expression Omnibus database. Using bioinformatics methods such as Weighted Gene Co-expression Network Analysis, Gene Ontology analysis, protein–protein interaction, and correlation, hub genes were identified. Using dot blot and N6-methyladenosine-IP-qPCR, the total and individual N6-methyladenosine gene levels were quantified. On clinical ovarian ectopic and eutopic endometrium tissues, N6-methyladenosine RNA methylation sequencing was performed. To authenticate protein localization and expression level, immunohistochemical staining and western blot were conducted, respectively. The database Connectivity Map was used to predict small molecules with potential therapeutic effects.
ResultsIn ovarian endometriosis, the N6-methyladenosine "reader" molecule IGF2BP2 and related target genes MEIS2 and GATA6 were highly expressed. IGF2BP2 promoted the proliferation, migration, and invasion of ectopic endometrial stromal cells by stabilizing the mRNA of MEIS2 and GATA6. Synergistically, METTL3 and IGF2BP2 increased the N6-methyladenosine methylation of MEIS2 and GATA6. We developed five molecules (Mercaptopurine, MK-886, CP-863187, Canadine, and Securinine) that could be used to treat ovarian endometriosis based on IGF2BP2.
ConclusionOur findings provided additional support for a systematized understanding of the role of N6-methyladenosine RNA methylation in endometriosis and confirmed for the first time the mechanism of IGF2BP2 in promoting ovarian endometriosis. This provides the molecular foundation for potential future therapies for ovarian endometriosis.
Data AvailabilityThe data used to support the findings of this study are available from the corresponding author upon request.
KeywordsOvarian endometriosis
IGF2BP2
MEIS2
GATA Binding Protein 6
N 6-methyladenosine
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