Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion
Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion
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DOI：
10.1073/pnas.0803574105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Lees, Jacqueline A.
中科院分区：
文献类型：
--
作者：
Dovey, Jennifer Shepard;Zacharek, Sima J.;Lees, Jacqueline A.
了解控制上皮癌发生的途径对开发有效的治疗方法至关重要。Polycomb家族成员Bmi1在许多上皮性肿瘤中过表达，但其在肿瘤发展中的作用尚未确定。我们现在显示Bmi1在肺腺癌中的关键作用。尽管肺发育在Bmi1缺陷小鼠中正常发生，但在致癌K-ras启动的肺癌小鼠模型中，Bmi1的缺失在非常早期的点降低了肺肿瘤的数量和进展。这与Bmi 1缺陷型推定细支气管肺泡干细胞（BASC）对致癌刺激的增殖能力缺陷相关。值得注意的是，在没有致癌K-ras的情况下，Bmi1缺陷型BASCs在培养中和体内肺损伤后显示出受损的增殖和自我更新能力。肺癌的发展和BASC的自我更新部分以p19（ARF）依赖的方式发生。我们的数据表明，Bmi1缺陷通过限制BASCs（明显的肺癌细胞来源）的扩增潜力来抑制肿瘤的发展。由于Bmi1在其他肿瘤类型中升高，这表明Bmi1在调节不同成人上皮组织中干细胞和肿瘤细胞的增殖中起关键作用。
Understanding the pathways that control epithelial carcinogenesis is vital to the development of effective treatments. The Polycomb group family member Bmi1 is overexpressed in numerous epithelial tumors, but its role in their development has not been established. We now show a key role for Bmi1 in lung adenocarcinoma. Whereas lung development occurs normally in Bmi1-deficient mice, loss of Bmi1 decreases the number and progression of lung tumors at a very early point in an oncogenic K-ras-initiated mouse model of lung cancer. This correlates with a defect in the ability of Bmi1-deficient putative bronchiolalveolar stem cells (BASCs) to proliferate in response to the oncogenic stimulus. Notably, in the absence of oncogenic K-ras, Bmi1-deficient BASCs show impaired proliferation and self-renewal capacity in culture and after lung injury in vivo. Abrogated lung cancer development and BASC self-renewal occur partially in a p19(ARF)-dependent manner. Our data suggest that Bmi1 deficiency suppresses tumor development by limiting the expansion potential of BASCs, the apparent lung cancer cells of origin. Because Bmi1 is elevated in additional tumor types, this suggests that Bmi1 plays a key role in regulating proliferation of both stem cells and tumor cells in diverse adult epithelial tissues.