The role of peroxisome proliferator-activated receptor gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. While PPARγ has been recently demonstrated to play non-cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of UC patient samples, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPARγ. Through genome-wide approaches including ChIP- and RNA-seq, we define a novel set of PPARγ-regulated genes in UC, including Sonic Hedgehog (SHH). Similar to PPARγ, genetic inhibition of SHH reduces -proliferation and motility. Finally, we demonstrate the PPARγ dependency of UC tumors in vivo by genetic and pharmacological PPARγ inhibition in subcutaneous xenografts. Collectively, our data indicate that PPARγ promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling. Implications: Genome wide analysis of DNA binding sites for oncogenic factor PPARγ revealed SHH as a novel downstream target involved in UC progression, providing important insight into the tumorigenic nature and molecular mechanism of PPARγ signaling in UC.

中文翻译：

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PPARγ在膀胱尿路上皮癌中的细胞内在致瘤功能

过氧化物酶体增殖物激活受体 γ (PPARγ) 在脂肪生成发育过程中的作用已得到很好的表征，但其在癌症亚型中的异常表达模式和功能却鲜为人知。虽然 PPARγ 最近已被证明在促进膀胱尿路上皮癌 (UC) 进展中发挥非细胞自主作用，但细胞内在致癌活性的潜在机制仍然未知。在这里，我们报告了 47% 的 UC 患者样本中 PPARγ 的稳健表达和核积累，超过了癌症基因组图谱公布的 mRNA 表达模式。体外试验首次揭示用 PPARγ 反向激动剂或通过 CRISPR-Cas9 敲除 PPARG 治疗 UC 细胞可减少多个已建立的 UC 细胞系的增殖、迁移和侵袭，在那些以 PPARG 基因组扩增或激活 RXRA（PPARγ 的专性异二聚体）突变为特征的患者中最为强烈。通过包括 ChIP 和 RNA-seq 在内的全基因组方法，我们在 UC 中定义了一组新的 PPARγ 调节基因，包括 Sonic Hedgehog (SHH)。与 PPARγ 相似，SHH 的遗传抑制减少了增殖和运动。最后，我们通过皮下异种移植物中的遗传和药理学 PPARγ 抑制证明了体内 UC 肿瘤的 PPARγ 依赖性。总的来说，我们的数据表明 PPARγ 至少部分通过与 SHH 信号传导相关的细胞自主机制促进部分患者的 UC 进展。启示：对致癌因子 PPARγ 的 DNA 结合位点的全基因组分析揭示了 SHH 作为参与 UC 进展的新型下游靶点，