Cargando…

PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin

Endometrial epithelia are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsuline...

Descripción completa

Detalles Bibliográficos
Autores principales: Wilson, Mike R., Harkins, Shannon, Reske, Jake J., Siwicki, Rebecca A., Adams, Marie, Bae-Jump, Victoria L., Teixeira, Jose M., Chandler, Ronald L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173629/
https://www.ncbi.nlm.nih.gov/pubmed/37170094
http://dx.doi.org/10.1186/s12958-023-01094-6
_version_ 1785039864243159040
author Wilson, Mike R.
Harkins, Shannon
Reske, Jake J.
Siwicki, Rebecca A.
Adams, Marie
Bae-Jump, Victoria L.
Teixeira, Jose M.
Chandler, Ronald L.
author_facet Wilson, Mike R.
Harkins, Shannon
Reske, Jake J.
Siwicki, Rebecca A.
Adams, Marie
Bae-Jump, Victoria L.
Teixeira, Jose M.
Chandler, Ronald L.
author_sort Wilson, Mike R.
collection PubMed
description Endometrial epithelia are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsulinemia also promotes cancer, but the direct action of insulin on mutated endometrial epithelial cells is unknown. Here, we treated 12Z endometriotic epithelial cells carrying the PIK3CA(H1047R) oncogene with insulin and examined transcriptomes by RNA-seq. While cells naively responded to insulin, the magnitude of differential gene expression (DGE) was nine times greater in PIK3CA(H1047R) cells, representing a synergistic effect between insulin signaling and PIK3CA(H1047R) expression. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in wild-type cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CA(H1047R) cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CA(H1047R) expression alone resulted in overexpression (OE) of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CA(H1047R) cells were rescued by knockdown of Viperin, while Viperin OE alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CA(H1047R) and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CA(H1047R) mutant cells. These results suggest that response to insulin signaling is altered in mutated endometriotic epithelial cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-023-01094-6.
format Online
Article
Text
id pubmed-10173629
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-101736292023-05-12 PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin Wilson, Mike R. Harkins, Shannon Reske, Jake J. Siwicki, Rebecca A. Adams, Marie Bae-Jump, Victoria L. Teixeira, Jose M. Chandler, Ronald L. Reprod Biol Endocrinol Research Endometrial epithelia are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsulinemia also promotes cancer, but the direct action of insulin on mutated endometrial epithelial cells is unknown. Here, we treated 12Z endometriotic epithelial cells carrying the PIK3CA(H1047R) oncogene with insulin and examined transcriptomes by RNA-seq. While cells naively responded to insulin, the magnitude of differential gene expression (DGE) was nine times greater in PIK3CA(H1047R) cells, representing a synergistic effect between insulin signaling and PIK3CA(H1047R) expression. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in wild-type cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CA(H1047R) cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CA(H1047R) expression alone resulted in overexpression (OE) of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CA(H1047R) cells were rescued by knockdown of Viperin, while Viperin OE alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CA(H1047R) and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CA(H1047R) mutant cells. These results suggest that response to insulin signaling is altered in mutated endometriotic epithelial cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12958-023-01094-6. BioMed Central 2023-05-11 /pmc/articles/PMC10173629/ /pubmed/37170094 http://dx.doi.org/10.1186/s12958-023-01094-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wilson, Mike R.
Harkins, Shannon
Reske, Jake J.
Siwicki, Rebecca A.
Adams, Marie
Bae-Jump, Victoria L.
Teixeira, Jose M.
Chandler, Ronald L.
PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
title PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
title_full PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
title_fullStr PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
title_full_unstemmed PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
title_short PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
title_sort pik3ca mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173629/
https://www.ncbi.nlm.nih.gov/pubmed/37170094
http://dx.doi.org/10.1186/s12958-023-01094-6
work_keys_str_mv AT wilsonmiker pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT harkinsshannon pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT reskejakej pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT siwickirebeccaa pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT adamsmarie pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT baejumpvictorial pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT teixeirajosem pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin
AT chandlerronaldl pik3camutationinendometrioticepithelialcellspromotesviperindependentinflammatoryresponsetoinsulin