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Oncogenic Determination of a Broad Spectrum of Phenotypes of Hepatocyte-Derived Mouse Liver Tumors.

Authors
  • Yamamoto, Masahiro1
  • Xin, Bing1
  • Watanabe, Kenji2
  • Ooshio, Takako1
  • Fujii, Kiyonaga1
  • Chen, Xi1
  • Okada, Yoko1
  • Abe, Hiroaki1
  • Taguchi, Yoshimitsu1
  • Miyokawa, Naoyuki3
  • Furukawa, Hiroyuki4
  • Nishikawa, Yuji5
  • 1 Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan. , (Japan)
  • 2 Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan. , (Japan)
  • 3 Department of Surgical Pathology, Asahikawa Medical University, Asahikawa, Japan. , (Japan)
  • 4 Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan. , (Japan)
  • 5 Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan. Electronic address: [email protected] , (Japan)
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Dec 01, 2017
Volume
187
Issue
12
Pages
2711–2725
Identifiers
DOI: 10.1016/j.ajpath.2017.07.022
PMID: 28964793
Source
Medline
License
Unknown

Abstract

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 for Afp, Dlk1, Nanog, and Sox2 and 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.

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