p53 and p16(Ink4a)/p19(Arf) Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells.
p53 and p16(Ink4a)/p19(Arf) Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells.
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DOI：
10.1016/j.neo.2016.08.003
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Du YN
中科院分区：
文献类型：
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作者：
Azzopardi S;Pang S;Klimstra DS;Du YN
在人类研究和小鼠模型中，p53和p16 Ink 4a/p19 Arf缺失的贡献在胰腺导管腺癌（PDAC）中得到了很好的确立。虽然在人胰腺腺泡细胞癌（PACC）和胰腺神经内分泌肿瘤（PanNET）中发现了功能性p53通路的缺失和Ink 4a/Arf的缺失，但它们在PACC和PanNET肿瘤发生中的直接作用仍有待确定。使用转基因小鼠模型表达病毒致癌基因多瘤中间T抗原（PyMT），我们证明，p53损失胰腺Pdx 1+祖细胞的结果在积极的PACC，而Ink 4a/Arf损失的结果在PanNET。p53和Ink 4a/Arf的同时丢失类似于单独的p53丢失，表明Ink 4a/Arf丢失对PACC进展没有累加效应。我们的研究结果表明，特定的肿瘤抑制基因型间接影响胰腺祖细胞的肿瘤生物学表型。此外，在β细胞增生的小鼠模型中，我们证明了p53和Ink 4a/Arf在抑制PanNET的进展中发挥协同作用。
In human studies and mouse models, the contributions of p53 and p16Ink4a/p19Arf loss are well established in pancreatic ductal adenocarcinoma (PDAC). Although loss of functional p53 pathway and loss of Ink4a/Arf in human pancreatic acinar cell carcinoma (PACC) and pancreatic neuroendocrine tumor (PanNET) are identified, their direct roles in tumorigenesis of PACC and PanNET remain to be determined. Using transgenic mouse models expressing the viral oncogene polyoma middle T antigen (PyMT), we demonstrate that p53 loss in pancreatic Pdx1+ progenitor cells results in aggressive PACC, whereas Ink4a/Arf loss results in PanNETs. Concurrent loss of p53 and Ink4a/Arf resembles loss of p53 alone, suggesting that Ink4a/Arf loss has no additive effect to PACC progression. Our results show that specific tumor suppressor genotypes provocatively influence the tumor biological phenotypes in pancreatic progenitor cells. Additionally, in a mouse model of β-cell hyperplasia, we demonstrate that p53 and Ink4a/Arf play cooperative roles in constraining the progression of PanNETs.