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Expression of type 2 orexin receptor in human endometrium and its epigenetic silencing in endometrial cancer
P Dehan1, C Canon, G Trooskens
1Department of Experimental Pathology, University of Liège, Tour de Pathologie (B23 + 4), Boulevard de l'Hôpital 1, B 4000 Liege Belgium. pierre.dehan@ulg.ac.be
Context:
Orexins A and B are neuropeptides that bind and activate 2 types of receptors. In addition to direct action in the brain, the orexinergic system has broader implications in peripheral organs, and it has been proposed to have a role in the induction of apoptosis. There are very few data on the endometrium.
Objective:
The expression and epigenetic regulation of type 2 orexin receptor (OX2R) was investigated in the human endometrium as well as in endometrial endometrioid carcinoma (EEC).
Methods:
OX2R localization was studied by immunohistochemistry in normal endometrium (n = 24) and in EEC (n = 32). The DNA methylation status of a CpG island located in the first exon of OX2R was analyzed by bisulfite sequencing in normal (n = 18), EEC (n = 34), and 3 endometrial cell lines. On the latter, mRNA expression and Western blotting as well as in vitro induction with orexin were performed.
Results:
Expression of the OX2R protein was detected in normal endometrial epithelia, whereas it was frequently lacking in EEC. This loss was associated with hypermethylation of OX2R in EEC in comparison with normal endometrium (median CpG methylation percentages of 48.85% and 5.85%, respectively). In cell lines, hypermethylation correlated with weak OX2R expression. Additionally, in vitro treatment of the 3 EEC cell lines with orexins A and B did not result in proliferation change
Conclusions:
Altogether our data provide evidence for the epigenetic silencing of OX2R in EEC. The implication of the OX2R loss in tumoral progression remains to be elucidated.
Insights
The type 2 orexin receptor (OX2R) is epigenetically silenced in endometrial endometrioid carcinoma (EEC) due to hypermethylation, leading to its loss. Further research is needed to understand its role in tumor progression.
Area of Science:
- Gynecology
- Molecular Biology
- Oncology
Background:
- Orexins A and B are neuropeptides with roles in the brain and peripheral organs, potentially influencing apoptosis.
- Limited data exist on the orexinergic system's function in the human endometrium.
Purpose of the Study:
- To investigate the expression and epigenetic regulation of the type 2 orexin receptor (OX2R) in normal human endometrium and endometrial endometrioid carcinoma (EEC).
Main Methods:
- Immunohistochemistry was used to assess OX2R protein localization in normal endometrium and EEC.
- Bisulfite sequencing analyzed DNA methylation of the OX2R gene's first exon CpG island.
- mRNA expression, Western blotting, and in vitro orexin treatment were performed on endometrial cell lines.
Main Results:
- OX2R protein was present in normal endometrial epithelia but frequently absent in EEC.
- EEC samples showed significant OX2R hypermethylation compared to normal endometrium.
- In cell lines, hypermethylation correlated with reduced OX2R expression, and orexin treatment did not affect proliferation.
Conclusions:
- Epigenetic silencing of OX2R via hypermethylation occurs in EEC.
- The precise role of OX2R loss in endometrial endometrioid carcinoma progression requires further investigation.
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