Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors.
Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors.
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DOI：
10.1016/j.ajpath.2017.07.022
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发表时间：
2017-12
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影响因子：
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通讯作者：
Masahiro Yamamoto;B. Xin;Kenji Watanabe;T. Ooshio;K. Fujii;Xi Chen;Yoko Okada;Hiroaki Abe;Yoshimitsu Taguchi;N. Miyokawa;H. Furukawa;Y. Nishikawa
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文献类型：
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作者：
Masahiro Yamamoto;B. Xin;Kenji Watanabe;T. Ooshio;K. Fujii;Xi Chen;Yoko Okada;Hiroaki Abe;Yoshimitsu Taguchi;N. Miyokawa;H. Furukawa;Y. Nishikawa
磷酸肌醇3-激酶-AKT、Yes相关蛋白（雅普）和MYC通路的激活参与人类肝癌，包括肝细胞癌（HCC）和胆管癌（CC）。然而，这些途径之间的相互作用的性质仍然知之甚少。在此，我们证明了这些途径的协调，在形成小鼠肝肿瘤诱导的肝细胞特异性体细胞整合豆蔻酰化AKT，突变雅普，Myc，或其组合。虽然单独引入雅普或Myc在诱导肿瘤方面是无效的，但是这些蛋白加速了由AKT诱导的肿瘤发生。所产生的肿瘤表现出各种组织学特征：AKT/Myc为低级别HCC，AKT/雅普为CC，AKT/Myc/雅普为高级别HCC。AKT/雅普诱导的CC与Notch通路的激活有关。有趣的是，Myc和雅普的组合产生的肿瘤由表达AFP、Dlk 1、Nanog和Sox 2 mRNA的肝母细胞/干细胞样细胞组成，偶尔形成未成熟的导管。最后，免疫组化分析显示，人HCC和CC分别主要与S6和糖原合成酶激酶-3 β的磷酸化相关，并且>60%的CC病例对磷酸化糖原合成酶激酶-3β和雅普均呈阳性。我们的研究表明，肝细胞来源的肿瘤表现出广泛的肿瘤表型，包括HCC，CC和肝母细胞瘤样，通过致癌途径的组合作用，磷酸肌醇3-激酶-AKT途径的状态是分化的关键决定因素。
Activation of the phosphoinositide 3-kinase–AKT, Yes-associated protein (YAP), and MYC pathways is involved in human liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). However, the nature of the interactions among these pathways has remained poorly understood. Herein, we demonstrate the coordination of these pathways during the formation of mouse liver tumors induced by hepatocyte-specific somatic integration of myristoylated AKT, mutant YAP, Myc, or their combinations. Although the introduction of YAP or Myc alone was inefficient in inducing tumors, these proteins accelerated tumorigenesis induced by AKT. The generated tumors demonstrated various histological features: low-grade HCC by AKT/Myc, CC by AKT/YAP, and high-grade HCC by AKT/Myc/YAP. CC induced by AKT/YAP was associated with activation of the Notch pathway. Interestingly, the combination of Myc and YAP generated tumors composed of hepatoblast/stem-like cells expressing mRNA forAfp,Dlk1,Nanog, andSox2and occasionally forming immature ducts. Finally, immunohistochemical analysis revealed that human HCC and CC were predominantly associated with phosphorylation of S6 and glycogen synthase kinase-3β, respectively, and >60% of CC cases were positive for both phosphorylated glycogen synthase kinase--3β and YAP. Our study suggests that hepatocyte-derived tumors demonstrate a wide spectrum of tumor phenotypes, including HCC, CC, and hepatoblastoma-like, through the combinatory effects of the oncogenic pathways and that the state of the phosphoinositide 3-kinase–AKT pathway is a key determinant of differentiation.