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
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Rb 和 p53 在胰腺神经内分泌肿瘤的发展中发挥不同的作用
DOI：
10.1158/0008-5472.can-19-2232
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发表时间：
2020
期刊：
影响因子：
11.2
通讯作者：
Seno Hiroshi
中科院分区：
文献类型：
--
作者：
Yamauchi Yuki;Kodama Yuzo;Uza Norimitsu;Masuda Atsuhiro;Tatsuoka Hisato;Masui Toshihiko;Inagaki Nobuya;Uemoto Shinji;Chiba Tsutomu;Seno Hiroshi
胰腺神经内分泌肿瘤（PanNET）于2017年被世界卫生组织分类为（G）1至3级，但PanNET启动和进展的确切机制仍不清楚。在这项研究中，我们使用基因工程小鼠模型来研究PanNET形成的机制。尽管小鼠的Rb基因（Pdx 1-Cre;Rbf/f）的胰腺特异性缺失不影响胰腺外分泌细胞，但在8月龄时胰岛细胞的α细胞/β细胞比率降低。在长期观察期间（18-20个月），小鼠形成分化良好的PanNET，Ki 67标记指数为2.7%。相比之下，胰腺特异性诱导ap 53突变（Pdx 1-Cre; Trp 53 R172 H）对胰腺外分泌和内分泌组织没有影响，但同时诱导ap 53突变和Rb基因缺失（Pdx 1-Cre; Trp 53 R172 H;Rbf/f）导致形成侵袭性PanNET，短期（4个月）Ki 67标记指数为24.7%。InPdx 1-Cre; Trp53R172H; Rbf/f小鼠中，胰岛细胞中mTOR通路的负调节因子Pten和Tsc 2的mRNA表达显著降低，并且在随后形成的PanNET中证实了mTOR通路的激活。因此，通过操纵Rbandp 53基因，我们在小鼠中建立了从异型增生胰岛到惰性PanNET和侵袭性转移PanNET的多步进展模型。这些观察结果表明，Rb和p53在PanNETs的发展中具有不同的作用。SignificancePancreas-specific操纵Rbandp 53基因诱导胰岛细胞恶性转化，从微腺瘤到惰性（1级）和随后的侵袭性PanNETs（2-3级）逐步进展。
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 theRbgene (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 ap53mutation (Pdx1-Cre;Trp53R172H) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of ap53mutation withRbgene deletion (Pdx1-Cre;Trp53R172H;Rbf/f) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). InPdx1-Cre;Trp53R172H;Rbf/fmice, mRNA expression ofPtenandTsc2, 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 manipulatingRbandp53genes, 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.SignificancePancreas-specific manipulation ofRbandp53genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2–3).