EZH2 and Endometrial Cancer Development: Insights from a Mouse Model.
EZH2 and Endometrial Cancer Development: Insights from a Mouse Model.
复制标题
EZH2和子宫内膜癌发展：来自小鼠模型的见解。
作者：
Fang X;Ni N;Wang X;Tian Y;Ivanov I;Rijnkels M;Bayless KJ;Lydon JP;Li Q
zeste 同源物增强子 2 (EZH2) 是多梳抑制复合物 2 的核心成分，在癌症发展中发挥着重要作用。由于 EZH2 的致癌和肿瘤抑制功能已在文献中记录，本研究的目的是确定 Ezh2 缺失对磷酸酶和张力蛋白同源物 (PTEN) 失活诱导的子宫内膜癌发生和进展的影响，PTEN 是子宫内膜癌患者中经常失调的抑癌基因。为此，我们使用由孕酮受体 (Pgr) 启动子驱动的 Cre 重组酶创建了子宫 Ezh2 和 Pten 缺失的小鼠。我们的结果显示 Ptend/d 的肿瘤负荷降低； Ezh2d/d 小鼠与 Ptend/d 小鼠在早期致癌过程中的比较。与 PTEN 缺失子宫相比，EZH2 和 PTEN 缺失子宫中 Ki67 指数降低，表明 EZH2 在早期肿瘤发展过程中具有致癌作用。然而，子宫 Ezh2 和 Pten 缺失的小鼠出现了不利的疾病结果，并伴有上皮分层加剧和炎症反应加剧。观察到的效应是非细胞自主的，并且是由免疫反应改变介导的，这由腔内中性粒细胞的大量积累所证明，这是 Ptend/d 中子宫内膜癌的一个标志；疾病进展期间的 Ezh2d/d 小鼠。因此，这些结果揭示了 EZH2 在子宫内膜癌发展中的双重作用。
Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, plays an important role in cancer development. As both oncogenic and tumor suppressive functions of EZH2 have been documented in the literature, the objective of this study is to determine the impact of Ezh2 deletion on the development and progression of endometrial cancer induced by inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene frequently dysregulated in endometrial cancer patients. To this end, we created mice harboring uterine deletion of both Ezh2 and Pten using Cre recombinase driven by the progesterone receptor (Pgr) promoter. Our results showed reduced tumor burden in Ptend/d; Ezh2d/d mice compared with that of Ptend/d mice during early carcinogenesis. The decreased Ki67 index in EZH2 and PTEN-depleted uteri versus that in PTEN-depleted uteri indicated an oncogenic role of EZH2 during early tumor development. However, mice harboring uterine deletion of both Ezh2 and Pten developed unfavorable disease outcome, accompanied by exacerbated epithelial stratification and heightened inflammatory response. The observed effect was non-cell autonomous and mediated by altered immune response evidenced by massive accumulation of intraluminal neutrophils, a hallmark of endometrial carcinoma in Ptend/d; Ezh2d/d mice during disease progression. Hence, these results reveal dual roles of EZH2 in endometrial cancer development.
登录
查看更多内容
影响因子：
--
作者：
Ihira K;Dong P;Xiong Y;Watari H;Konno Y;Hanley SJ;Noguchi M;Hirata N;Suizu F;Yamada T;Kudo M;Sakuragi N
通讯作者：
Sakuragi N
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Kim, Minkyu;Park, Jisoo;Bouhaddou, Mehdi;Kim, Kyumin;Rojc, Ajda;Modak, Maya;Soucheray, Margaret;McGregor, Michael J.;O'Leary, Patrick;Wolf, Denise;Stevenson, Erica;Foo, Tzeh Keong;Mitchell, Dominique;Herrington, Kari A.;Munoz, Denise P.;Tutuncuoglu, Beril;Chen, Kuei-Ho;Zheng, Fan;Kreisberg, Jason F.;Diolaiti, Morgan E.;Gordan, John D.;Coppe, Jean-Philippe;Swaney, Danielle L.;Xia, Bing;van 't Veer, Laura;Ashworth, Alan;Ideker, Trey;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
影响因子：
4
作者：
Fang, Xin;Ni, Nan;Li, Qinglei
通讯作者：
Li, Qinglei
影响因子：
3.6
作者：
Filant J;DeMayo FJ;Pru JK;Lydon JP;Spencer TE
通讯作者：
Spencer TE