Bmi1通过一种不依赖Ink4a的机制对胰腺癌的起始是必需的。
Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism.
作者信息
Bednar Filip, Schofield Heather K, Collins Meredith A, Yan Wei, Zhang Yaqing, Shyam Nikhil, Eberle Jaime A, Almada Luciana L, Olive Kenneth P, Bardeesy Nabeel, Fernandez-Zapico Martin E, Nakada Daisuke, Simeone Diane M, Morrison Sean J, Pasca di Magliano Marina
机构信息
Department of Surgery.
Program in Cell and Molecular Biology, Medical Scientist Training Program.
出版信息
Carcinogenesis. 2015 Jul;36(7):730-8. doi: 10.1093/carcin/bgv058. Epub 2015 May 4.
Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.
表观遗传失调参与了许多上皮性癌症的发生和发展。BMI1是多梳蛋白家族的一个组成部分，通过控制组蛋白泛素化和多个基因组位点的长期抑制，在这些过程中发挥关键作用。BMI1此前已被证明与胰腺内环境稳定及胰腺癌干细胞功能有关。然而，尚无研究探讨其在胰腺癌发生早期阶段的作用。在此，我们利用一种新型的Bmi1条件性敲除技术，结合Kras（G12D）驱动的胰腺癌小鼠模型，表明BMI1是小鼠胰腺肿瘤发生起始所必需的。我们还证明，Bmi1在胰腺癌发生过程中的需求独立于Ink4a/Arf基因座，并且至少部分由活性氧的失调介导。我们的数据为这种表观遗传调节因子在胰腺癌发生中的重要性提供了新的证据。
Zotero 插件