当前位置： SCI文献检索 > CANCER RESEARCH期刊下所有文献 > Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.

Abstract：

:Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 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;Rbf/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 islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET. SIGNIFICANCE: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).

journal_name

Cancer Res

journal_title

Cancer research

authors

Yamauchi Y,Kodama Y,Shiokawa M,Kakiuchi N,Marui S,Kuwada T,Sogabe Y,Tomono T,Mima A,Morita T,Matsumori T,Ueda T,Tsuda M,Nishikawa Y,Kuriyama K,Sakuma Y,Ota Y,Maruno T,Uza N,Masuda A,Tatsuoka H,Yabe D,Minamiguc

doi

10.1158/0008-5472.CAN-19-2232

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

3620-3630

issue

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-19-2232

journal_volume

pub_type

杂志文章

在线工具

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.