PDF(Pubmed)
Abstract：
BACKGROUND: The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC.
METHODS: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients.
RESULTS: In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence.
CONCLUSIONS: An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.
METHODS: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients.
RESULTS: In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence.
CONCLUSIONS: An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.
摘要：
背景：结直肠癌（CRC）的间质亚型，与不良预后相关，其特征在于细胞朊病毒蛋白PrPC的大量表达，其代表候选治疗靶标。如何在CRC中诱导PrPC仍然难以捉摸。这项研究旨在阐明控制PrPC表达的信号通路，并阐明与PrPC相关的基因调控网络。
方法：我们对不同的体外数据集进行了计算机模拟分析，小鼠CRC和患者队列的离体和体内模型。我们挖掘了ChIPseq研究并进行了启动子分析。通过遗传和药理学方法操纵CRC细胞系。我们创建了结合肠上皮细胞中Apc的条件性失活和人朊病毒蛋白基因PRNP的过表达的小鼠。在两项随机对照试验中进行了生物信息学分析，总计超过3000例CRC患者。
结果：在电脑分析结合基于细胞的测定确定Wnt-β-连环蛋白和糖皮质激素途径为PRNP表达的上游调节因子，小鼠和人类之间的细微差异。我们发现了PrPC和这两种途径之间的多个反馈回路，这转化为小鼠CRC发病机制的恶化。在III期CRC患者中，由PRNP-CTNNB1-NR3C1定义的签名，编码PrPC，β-连环蛋白和糖皮质激素受体，在不良预后中代表过多，间充质亚型与减少复发时间的相关性。
结论：释放的PrPC依赖性恶性循环是预后不良的病因学，间充质CRC。来自这种侵袭性CRC亚型的患者可以受益于靶向PRNP-CTNNB1-NR3C1轴的治疗。
方法：我们对不同的体外数据集进行了计算机模拟分析，小鼠CRC和患者队列的离体和体内模型。我们挖掘了ChIPseq研究并进行了启动子分析。通过遗传和药理学方法操纵CRC细胞系。我们创建了结合肠上皮细胞中Apc的条件性失活和人朊病毒蛋白基因PRNP的过表达的小鼠。在两项随机对照试验中进行了生物信息学分析，总计超过3000例CRC患者。
结果：在电脑分析结合基于细胞的测定确定Wnt-β-连环蛋白和糖皮质激素途径为PRNP表达的上游调节因子，小鼠和人类之间的细微差异。我们发现了PrPC和这两种途径之间的多个反馈回路，这转化为小鼠CRC发病机制的恶化。在III期CRC患者中，由PRNP-CTNNB1-NR3C1定义的签名，编码PrPC，β-连环蛋白和糖皮质激素受体，在不良预后中代表过多，间充质亚型与减少复发时间的相关性。
结论：释放的PrPC依赖性恶性循环是预后不良的病因学，间充质CRC。来自这种侵袭性CRC亚型的患者可以受益于靶向PRNP-CTNNB1-NR3C1轴的治疗。
