Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver
Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver
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DOI：
10.1073/pnas.0911427107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Johnson, Randy L.
中科院分区：
文献类型：
--
作者：
Lu, Li;Li, Ying;Johnson, Randy L.
哺乳动物的器官大小是如何控制的，目前还不清楚。在果蝇中，Hippo信号通路的功能是抑制成虫盘的生长，并被认为控制器官的大小。为了研究河马信号在调节哺乳动物器官大小中的作用，我们分别产生了果蝇萨尔瓦多和河马的直向同源物Sav 1、mst 1和mst 2的条件等位基因。肝细胞中mst 1和mst 2的特异性缺失导致由于过度增殖而导致的显著增大的肝脏。到5-6个月大时，mst 1/2条件突变肝脏具有多个肝肿瘤病灶，表明mst 1和mst 2的联合活性在肝细胞中充当多余的肿瘤抑制因子。肝脏特异性缺失Sav 1也获得了类似的发现，Sav 1是第二个核心Hippo信号成分，有助于激活mst 1和mst 2。肿瘤从sav 1突变体表现出不同的形态，表明肿瘤起始细胞的混合谱系起源。mst 1/2和sav 1条件突变体的肝组织的转录谱显示了Hippo信号调节基因的网络，其特异性富集了参与免疫和炎症反应的基因。mst 1/2双突变肝组织的组织学和免疫学特征显示，在导管周围区域有大量的称为卵圆细胞的成体兼性干细胞的积累。由于卵圆细胞的诱导通常与肝损伤和肿瘤形成有关，因此这些细胞可能有助于我们在sav 1和mst 1/2突变体中观察到的肝脏肿大和肝癌。总之，我们的研究结果表明，海马信号通路是哺乳动物肝脏生长的关键调节因子，也是肝脏肿瘤形成的有效抑制因子。
How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional alleles of Sav1, mst1, and mst2, orthologs of Drosophila Salvador and hippo, respectively. Specific deletion of both mst1 and mst2 in hepatocytes results in significantly enlarged livers due to excessive proliferation. By the age of 5-6 months, mst1/2 conditional mutant livers have multiple foci of liver tumors, indicating that the combined activities of mst1 and mst2 act as redundant tumor suppressors in hepatocytes. Similar findings were obtained with liver-specific deletion of Sav1, a second core Hippo signaling component that facilitates activation of mst1 and mst2. Tumors from sav1 mutants exhibited varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional mutants revealed a network of Hippo signaling regulated genes with specific enrichment for genes involved in immune and inflammatory responses. Histological and immunological characterization of mst1/2 double mutant liver tissues revealed abundant accumulation of adult facultative stem cells termed oval cells in periductal regions. Because oval cells induction is commonly associated with liver injury and tumor formation, it is likely that these cells contribute to the enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken together, our results demonstrate that the Hippo signaling pathway is a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation.