論文

査読有り 国際誌
2020年6月26日

Rb and p53 execute distinct roles in the development of pancreatic neuroendocrine tumors.

Cancer research
  • Yuki Yamauchi
  • ,
  • Yuzo Kodama
  • ,
  • Masahiro Shiokawa
  • ,
  • Nobuyuki Kakiuchi
  • ,
  • Saiko Marui
  • ,
  • Takeshi Kuwada
  • ,
  • Yuko Sogabe
  • ,
  • Teruko Tomono
  • ,
  • Atsushi Mima
  • ,
  • Toshihiro Morita
  • ,
  • Tomoaki Matsumori
  • ,
  • Tatsuki Ueda
  • ,
  • Motoyuki Tsuda
  • ,
  • Yoshihiro Nishikawa
  • ,
  • Katsutoshi Kuriyama
  • ,
  • Yojiro Sakuma
  • ,
  • Yuji Ota
  • ,
  • Takahisa Maruno
  • ,
  • Norimitsu Uza
  • ,
  • Atsuhiro Masuda
  • ,
  • Hisato Tatsuoka
  • ,
  • Daisuke Yabe
  • ,
  • Sachiko Minamiguchi
  • ,
  • Toshihiko Masui
  • ,
  • Nobuya Inagaki
  • ,
  • Shinji Uemoto
  • ,
  • Tsutomu Chiba
  • ,
  • Hiroshi Seno

開始ページ
canres.2232.2019
終了ページ
canres.2232.2019
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/0008-5472.CAN-19-2232
出版者・発行元
American Association for Cancer Research (AACR)

Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1-3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f) in mice did not affect pancreatic exocrine cells, the α-cell/β-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rb f/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islets to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET.

リンク情報
DOI
https://doi.org/10.1158/0008-5472.CAN-19-2232
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32591410
URL
https://syndication.highwire.org/content/doi/10.1158/0008-5472.CAN-19-2232

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