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Project description:Endometrial epithelia (EE) 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 EE is unknown. Here, we treated EE cells carrying the PIK3CAH1047R oncogene with insulin and examined differential transcriptomes by RNA-seq. While cells responded to insulin, the magnitude of differential gene expression (DGE) was 9 times greater in PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in normal cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R expression alone resulted in fewer differentially expressed genes, however, top among these was overexpression of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CAH1047R cells were rescued by knockdown of Viperin, while overexpression alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest a differential response to insulin signaling in mutated EE.
2023-05-09 | GSE215259 | GEO
Project description:Endometrial epithelia (EE) 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 EE is unknown. Here, we treated EE cells carrying the PIK3CAH1047R oncogene with insulin and examined differential transcriptomes by RNA-seq. While cells responded to insulin, the magnitude of differential gene expression (DGE) was 9 times greater in PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in normal cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R expression alone resulted in fewer differentially expressed genes, however, top among these was overexpression of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CAH1047R cells were rescued by knockdown of Viperin, while overexpression alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest a differential response to insulin signaling in mutated EE.
2023-05-09 | GSE215258 | GEO
Project description:Endometrial epithelia (EE) 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 EE is unknown. Here, we treated EE cells carrying the PIK3CAH1047R oncogene with insulin and examined differential transcriptomes by RNA-seq. While cells responded to insulin, the magnitude of differential gene expression (DGE) was 9 times greater in PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in normal cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R expression alone resulted in fewer differentially expressed genes, however, top among these was overexpression of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CAH1047R cells were rescued by knockdown of Viperin, while overexpression alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest a differential response to insulin signaling in mutated EE.
2023-05-09 | GSE215257 | GEO
Project 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 PIK3CAH1047R 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 PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R 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 PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R 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 PIK3CAH1047R 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 PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest that response to insulin signaling is altered in mutated endometriotic epithelial cells.
| S-EPMC10173629 | biostudies-literature
Project description:PIK3CA mutation in endometrial epithelia promotes Viperin-dependent inflammatory response to insulin
| PRJNA889440 | ENA
Project description:PIK3CA mutation in endometrial epithelia promotes Viperin-dependent inflammatory response to insulin 2
| PRJNA889544 | ENA
Project description:PIK3CA mutation in endometrial epithelia promotes Viperin-dependent inflammatory response to insulin 1
| PRJNA889545 | ENA
Project description:PIK3CA mutation in endometrial epithelia promotes Viperin-dependent inflammatory response to insulin 3
| PRJNA889546 | ENA
Project description:BackgroundIn addition to genomic risk variants and environmental influences, increasing evidence suggests epigenetic modifications are important for orofacial development and their alterations can contribute to orofacial clefts. Ezh2 encodes a core catalytic component of the Polycomb repressive complex responsible for addition of methyl marks to Histone H3 as a mechanism of repressing target genes. The role of Ezh2 in orofacial clefts remains unknown.AimsTo investigate the epithelial role of Ezh2-dependent methylation in secondary palatogenesis.MethodsWe used conditional gene-targeting methods to ablate Ezh2 in the surface ectoderm-derived oral epithelium of mouse embryos. We then performed single-cell RNA sequencing combined with immunofluorescence and RT-qPCR to investigate gene expression in conditional mutant palate. We also employed double knockout analyses of Ezh1 and Ezh2 to address if they have synergistic roles in palatogenesis.ResultsWe found that conditional inactivation of Ezh2 in oral epithelia results in partially penetrant cleft palate. Double knockout analyses revealed that another family member Ezh1 is dispensable in orofacial development, and it does not have synergistic roles with Ezh2 in palatogenesis. Histochemistry and single-cell RNA-seq analyses revealed dysregulation of cell cycle regulators in the palatal epithelia of Ezh2 mutant mouse embryos disrupts palatogenesis.ConclusionEzh2-dependent histone H3K27 methylation represses expression of cell cycle regulator Cdkn1a and promotes proliferation in the epithelium of the developing palatal shelves. Loss of this regulation may perturb movement of the palatal shelves, causing a delay in palate elevation which may result in failure of the secondary palate to close altogether.
| S-EPMC10784412 | biostudies-literature
Project description:Inflammatory breast cancer (IBC) is an aggressive BC subtype with poor outcomes. A targetable somatic PIK3CA mutation is reported in 30% of IBC, allowing for treatment by PI3Kα-specific inhibitors, such as alpelisib. The aim of this study was to evaluate the detection rate of circulating PIK3CA mutation in locally-advanced IBC (LAIBC) patients harbouring a PIK3CA mutation on initial biopsy. This monocentric retrospective study was based on available stored plasma samples and tumour biopsies at diagnosis from all LAIBC patients treated with neo-adjuvant chemotherapy (NCT) between 2008 and 2018 at the Centre Henri Becquerel. PIK3CA mutations (E542K, E545K, H1047R/L) were assessed by droplet digital PCR (ddPCR) in plasma samples and tumoral tissue at diagnosis. A total of 55 patients were included. Overall, 14/55 patients (25%) had a PIK3CA mutation identified on baseline biopsy (H1047R = 8; H1047L = 3; E545K = 2; E542K = 1). Among them, 11 (79%) patients had enough DNA for circulating DNA analyses, and corresponding circulating PIK3CA mutations were found in 6/11 (55%). Among the 41 patients without PIK3CA mutations on biopsy, 32 (78%) had enough DNA for circulating DNA analysis, and no circulating PIK3CA mutation was identified. Our results revealed no prognostic or predictive value of PIK3CA mutations at the diagnosis of non-metastatic IBC but highlighted the prognostic value of the cfDNA rate at diagnosis. Our study showed that a corresponding circulating PIK3CA mutation was identified in 55% of LAIBC patients with PIK3CA-mutated tumours, while no circulating mutation was found among patients with PI3KCA wild-type tumours.
| S-EPMC8674263 | biostudies-literature