Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer.
Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer.
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DOI：
10.1038/onc.2013.333
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发表时间：
2014-07-10
期刊：
影响因子：
8
通讯作者：
Lees JA
中科院分区：
文献类型：
--
作者：
Maynard MA;Ferretti R;Hilgendorf KI;Perret C;Whyte P;Lees JA
表观遗传调节因子 BMI1 在包括结直肠癌在内的多种人类肿瘤中逐渐上调。在这项研究中，我们使用本地小鼠模型评估了肠道肿瘤发生中 Bmi1 的需求，其中 Apc 在肠道上皮中被条件性消融。 Bmi1 的种系突变显着减少了该模型中小肠腺瘤的数量和大小，并且其作用呈剂量依赖性。此外，与野生型对照相比，Bmi1−/− 小鼠在 3 至 4 个月龄之间，肿瘤大小中值没有增加，肿瘤数量显着减少。因此，Bmi1 对于小肠腺瘤的进展和维持都是必需的。重要的是，Bmi1 缺陷不会破坏 Apc 失活引起的致癌事件。相反，Arf 肿瘤抑制因子（Bmi1 表观遗传沉默的已知靶点）在 Bmi1 突变肿瘤中表达上调。这伴随着 p53 的显着上调，经测序证实其为野生型，并且最小的 Bmi1−/− 腺瘤内的细胞凋亡也增加。通过将 Arf 引入该癌症模型，我们发现 Arf 是诱导 p53 和细胞凋亡所必需的，并且它是 Bmi1 缺陷抑制肠道肿瘤发生能力的关键决定因素。最后，生成了条件性 Bmi1 突变株，并用于确定在肠上皮内特异性删除 Bmi1 的后果。引人注目的是，肠道特异性 Bmi1 缺失以与种系 Bmi1 缺失无法区分的方式抑制小肠腺瘤。因此，我们得出结论，Bmi1 缺陷以细胞自主和高度 Arf 依赖性的方式损害小肠肿瘤的进展和维持。
The epigenetic regulator BMI1 is upregulated progressively in a wide variety of human tumors including colorectal cancer. In this study, we assessed the requirement for Bmi1 in intestinal tumorigenesis using an autochthonous mouse model in which Apc was conditionally ablated in the intestinal epithelium. Germline mutation of Bmi1 significantly reduced both the number and size of small intestinal adenomas arising in this model, and it acted in a dose-dependent manner. Moreover, in contrast to wildtype controls, Bmi1−/− mice showed no increase in median tumor size, and a dramatic decrease in tumor number, between 3 and 4 months of age. Thus, Bmi1 is required for both progression and maintenance of small intestinal adenomas. Importantly, Bmi1 deficiency did not disrupt oncogenic events arising from Apc inactivation. Instead, the Arf tumor suppressor, a known target of Bmi1 epigenetic silencing, was upregulated in Bmi1 mutant tumors. This was accompanied by significant upregulation of p53, which was confirmed by sequencing to be wildtype, and also elevated apoptosis within the smallest Bmi1−/− adenomas. By crossing Arf into this cancer model, we showed that Arf is required for the induction of both p53 and apoptosis, and it is a key determinant of the ability of Bmi1 deficiency to suppress intestinal tumorigenesis. Finally, a conditional Bmi1 mutant strain was generated and used to determine the consequences of deleting Bmi1 specifically within the intestinal epithelium. Strikingly, intestinal-specific Bmi1 deletion suppressed small intestinal adenomas in a manner that was indistinguishable from germline Bmi1 deletion. Thus, we conclude that Bmi1 deficiency impairs the progression and maintenance of small intestinal tumors in a cell autonomous and highly Arf-dependent manner.
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影响因子：
30.8
作者：
Sangiorgi, Eugenio;Capecchi, Mario R.
通讯作者：
Capecchi, Mario R.
影响因子：
5.3
作者：
Abdouh, Mohamed;Facchino, Sabrina;Bernier, Gilbert
通讯作者：
Bernier, Gilbert
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
5
作者：
Colnot, S;Niwa-Kawakita, M;Perret, C
通讯作者：
Perret, C
影响因子：
2.9
作者：
Gieni, Randall S.;Hendzel, Michael J.
通讯作者：
Hendzel, Michael J.