PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin.
PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin.
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DOI：
10.1186/s12958-023-01094-6
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发表时间：
2023-05-11
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已知子宫内膜上皮在没有任何病理学的情况下具有癌症驱动突变，包括PIK 3CA中的突变。胰岛素在妊娠期间调节子宫代谢中起着重要作用，高胰岛素血症与影响生育力的疾病有关。高胰岛素血症也促进癌症，但胰岛素对突变的子宫内膜上皮细胞的直接作用尚不清楚。在这里，我们用胰岛素处理了携带PIK 3CAH 1047 R癌基因的12 Z增生上皮细胞，并通过RNA-seq检查了转录组。当细胞对胰岛素有天然反应时，PIK 3CAH 1047 R细胞中差异基因表达（DGE）的幅度是9倍，这表明胰岛素信号传导和PIK 3CAH 1047 R表达之间存在协同效应。干扰素信号转导和未折叠蛋白反应（UPR）是受影响基因中富集的途径。野生型细胞中的胰岛素处理激活了正常的内质网应激（ERS）反应程序，而PIK 3CAH 1047 R细胞激活了避免ERS诱导的细胞凋亡所必需的程序。PIK 3CAH 1047 R单独表达导致Viperin（RSAD 2）的过表达（OE），其参与病毒应答并在妊娠早期在子宫内膜中上调。PIK 3CAH 1047 R细胞中胰岛素诱导的转录变化通过Viperin的敲低而得到挽救，而单独的Viperin OE不足以诱导对胰岛素的DGE应答，这表明Viperin对于PIK 3CAH 1047 R和胰岛素处理的协同效应是必要的但不是充分的。我们鉴定了干扰素信号传导、病毒应答和蛋白质靶向途径，这些途径由胰岛素诱导，但依赖于PIK 3CAH 1047 R突变细胞中的Viperin。这些结果表明，胰岛素信号的反应改变了突变的上皮细胞。在线版本包含补充材料，可通过10.1186/s12958-023-01094-6获得。
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. The online version contains supplementary material available at 10.1186/s12958-023-01094-6.
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作者：
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通讯作者：
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发表时间：
2009-10-06
影响因子：
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