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首页> 外文期刊>Molecular and Cellular Biology >Obligate Roles for p16~(Ink4a) and p19~(Arf)-p53 in the Suppression of Murine Pancreatic Neoplasia
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Obligate Roles for p16~(Ink4a) and p19~(Arf)-p53 in the Suppression of Murine Pancreatic Neoplasia

机译：p16~（Ink4a） 和 p19~（Arf）-p53 在抑制小鼠胰腺肿瘤中的专性作用

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Epithelial tumors of the pancreas exhibit a wide spectrum of histologies with varying propensities for metastasis and tissue invasion. The histogenic relationship among these tumor types is not well established; moreover, the specific role of genetic lesions in the progression of these malignancies is largely undefined. Transgenic mice with ectopic expression of transforming growth factor alpha (TGF-α) in the pancreatic acinar cells develop tubular metaplasia, a potential premalignant lesion of the pancreatic ductal epithelium. To evaluate the cooperative interactions between TGF-α and signature mutations in pancreatic tumor genesis and progression, TGFα transgenic mice were crossed onto Ink4a/Arf and/or p53 mutant backgrounds. These compound mutant mice developed a novel pancreatic neoplasm, serous cystadenoma (SCA), presenting as large epithelial tumors bearing conspicuous gross and histological resemblances to their human counterpart. TGFα animals heterozygous for both the Ink4a/Arf and the p53 mutation showed a dramatically increased incidence of SCA, indicating synergistic interaction of these alleles. Inactivation of p16~(Ink4a) by loss of heterozygosity, intragenic mutation, or promoter hypermethylation was a common feature in these SCAs, and correspondingly, none of the tumors expressed wild-type p16~(Ink4a). All tumors sustained loss of p53 or Arf, generally in a mutually exclusive fashion. The tumor incidence data and molecular profiles establish a pathogenic role for the dual inactivation of p16~(Ink4a) and p19~(Arf)-p53 in the development of SCA in mice, demonstrating that p16~(Ink4a) is a murine tumor suppressor. This genetically defined model provides insights into the molecular pathogenesis of SCA and serves as a platform for dissection of cell-specific programs of epithelial tumor suppression.
机译：胰腺上皮肿瘤表现出广泛的组织学特征，具有不同的转移和组织侵袭倾向。这些肿瘤类型之间的组织致关系尚未得到充分证实;此外，遗传病变在这些恶性肿瘤进展中的具体作用在很大程度上是不确定的。在胰腺腺泡细胞中具有转化生长因子α（TGF-α）异位表达的转基因小鼠发生肾小管化生，这是胰腺导管上皮的潜在癌前病变。为了评估 TGF-α 与胰腺肿瘤发生和进展中标志性突变之间的协同相互作用，将 TGFα 转基因小鼠杂交到 Ink4a/Arf 和/或 p53 突变体背景上。这些复合突变小鼠发展出一种新的胰腺肿瘤，浆液性囊腺瘤（SCA），表现为大的上皮肿瘤，与人类对应物具有明显的肉眼和组织学相似性。Ink4a/Arf 和 p53 突变杂合子的 TGFα 动物显示 SCA 的发生率显着增加，表明这些等位基因之间存在协同相互作用。通过杂合性缺失、基因内突变或启动子高甲基化使p16~（Ink4a）失活是这些SCA的共同特征，相应地，没有一个肿瘤表达野生型p16~（Ink4a）。所有肿瘤都持续 p53 或 Arf 的缺失，通常以相互排斥的方式。肿瘤发病率数据和分子谱确定了p16~（Ink4a）和p19~（Arf）-p53在小鼠SCA发生中的双重失活的致病作用，表明p16~（Ink4a）是小鼠抑癌基因。这种遗传定义的模型提供了对SCA分子发病机制的见解，并可作为解剖上皮肿瘤抑制细胞特异性程序的平台。

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