Disruption of PPARgamma signaling results in mouse prostatic intraepithelial neoplasia involving active autophagy.
Disruption of PPARgamma signaling results in mouse prostatic intraepithelial neoplasia involving active autophagy.
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DOI：
10.1038/cdd.2009.148
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发表时间：
2010-03
影响因子：
12.4
通讯作者：
Hayward, S. W.
中科院分区：
文献类型：
--
作者：
Jiang, M.;Fernandez, S.;Jerome, W. G.;He, Y.;Yu, X.;Cai, H.;Boone, B.;Yi, Y.;Magnuson, M. A.;Roy-Burman, P.;Matusik, R. J.;Shappell, S. B.;Hayward, S. W.
关键词：
过氧化物酶体增殖物激活受体-γ（peroxisome proliferator-activated receptor-gamma，PPAR γ）调节细胞脂质代谢、氧化还原状态和细胞器分化之间的界面。在小鼠中，条件性的PPAR γ基因敲除前列腺上皮导致局灶性增生，其发展为小鼠前列腺上皮内瘤变（mPIN）。PIN分级随时间延长而加重。电子显微镜（EM）显示累积的次级溶酶体含有细胞器和碎片，提示自噬。与该分析一致，发现自噬标志物LC 3在PPAR γ KO组织中的PIN区域中上调。我们选择性地敲低野生型小鼠前列腺上皮细胞中的PPAR γ 2亚型，并在组织重组模型中检查其结果。组织学上移植的组织类似于条件性PPAR γ KO小鼠前列腺。体外PPAR γ和PPAR γ 2缺陷上皮细胞的EM研究提示自噬，与前列腺组织分析一致。这通过检查beclin-1和LC 3的表达得到证实。在PPAR γ/γ 2缺陷细胞中的基因表达谱表明，与过氧化物酶体和溶酶体成熟、脂质氧化和降解相关的细胞周期控制和代谢信号网络的主要失调。通过γ 1或γ 2亚型的再表达，可以挽救PPAR γ缺陷细胞的假定自噬表型。我们的结论是，在mPIN发病过程中，PPAR γ信号转导的破坏导致自噬和氧化应激。
Peroxisome proliferator-activated receptor-gamma (PPARγ) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Conditional prostatic epithelial knockout of PPARγ in mice resulted in focal hyperplasia which developed into mouse prostatic intraepithelial neoplasia (mPIN). The grade of PIN became more severe with time. Electron microscopy (EM) showed accumulated secondary lysosomes containing cellular organelles and debris suggestive of autophagy. Consistent with this analysis the autophagy marker LC3 was found to be upregulated in areas of PIN in PPARγ KO tissues. We selectively knocked down PPARγ2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically grafted tissues resembled the conditional PPARγ KO mouse prostates. EM studies of PPARγ- and PPARγ2-deficient epithelial cells in vitro were suggestive of autophagy, consistent with the prostatic tissue analysis. This was confirmed by examining expression of beclin-1 and LC3. Gene expression profiling in PPARγ-/γ2-deficient cells indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. The putative autophagic phenotypes of PPARγ-deficient cells could be rescued by re-expression of either γ1 or γ2 isoform. We conclude that disruption of PPARγ signaling results in autophagy and oxidative stress during mPIN pathogenesis.
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