PrP(C) Promotes Endometriosis Progression by Reprogramming Cholesterol Metabolism and Estrogen Biosynthesis of Endometrial Stromal Cells through PPARα Pathway.
PrP(C) Promotes Endometriosis Progression by Reprogramming Cholesterol Metabolism and Estrogen Biosynthesis of Endometrial Stromal Cells through PPARα Pathway.
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DOI：
10.7150/ijbs.68015
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发表时间：
2022
影响因子：
9.2
通讯作者：
Zhao D
中科院分区：
文献类型：
--
作者：
Peng HY;Lei ST;Hou SH;Weng LC;Yuan Q;Li MQ;Zhao D
子宫内膜异位症(EMS)是一种雌激素依赖性疾病。然而，在子宫内膜异位症病变中激活雌激素生物合成的潜在机制在很大程度上是未知的。我们通过对GEO数据集的生物信息分析，分析了EMS病变的胆固醇代谢和雌激素生物合成状况，并通过使用PRNP基因敲除小鼠(PRNP-/-，KO119)供体子宫片段、PRNP基因敲除小鼠八肽重复区(KO120)和PRNP转基因小鼠(Tg20)供体子宫片段构建了体内外EMS模型。我们发现，EMS患者胆固醇代谢和雌激素转换酶的转录组受到干扰，EMS皮损中细胞胆固醇浓度和局部雌二醇水平显著升高，以及高水平的PrPC，由PRNP编码。值得注意的是，17-β雌二醇刺激显著上调了子宫内膜间质细胞中PrPC的表达，PrPC促进了ESC的增殖、迁移和侵袭能力，并进一步在小鼠模型中被证实加速了EMS的进展。更重要的是，PrPC以PPARα途径依赖的方式促进胚胎干细胞的胆固醇积累和雌激素的生物合成。综上所述，本研究提示PrPC-胆固醇代谢/雌激素生物合成通过负性调节PPARα途径参与EMS的进展，可能成为EMS干预的潜在治疗靶点。
Endometriosis (EMs) is characterized as an estrogen-dependent disease. Whereas, the underlying mechanism for activated estrogen biosynthesis in EMs lesions is largely unknown. We analyzed cholesterol metabolism and estrogen biosynthesis condition of EMs lesions by biological information analysis of GEO datasets, and further verified both in vitro and in vivo by constructing EMs models with uterus fragments from donors of PRNP knockout mouse (Prnp-/-, KO119), Octapeptide repeat region of PRNP knockout mouse (KO120) and PRNP transgenic mouse (Tg20). We found that transcriptome of cholesterol metabolism and estrogen-converting enzymes were disturbed in EMs patients, and cellular cholesterol concentration and local estradiol level were substantially increased in EMs lesions, as well as the high level of prion (PrPC, encoded by PRNP). Notably, 17-β estradiol stimulation significantly up-regulated PrPC expression in endometrial stromal cells (ESC) and PrPC promoted the proliferative, migratory and invasive abilities of ESC, and was further verified to accelerate EMs progression in mouse models. More importantly, PrPC promoted cholesterol accumulation and activated estrogen biosynthesis of ESC in a PPARα pathway-dependent manner. Taken together, this study suggests that PrPC-cholesterol metabolism/estrogen biosynthesis contributes to the progression of EMs by negatively regulating PPARα pathway, and could be potential therapeutic targets for EMs intervention.
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