Inactivation of srnad4 accelerates KrasG12D-Mediated pancreatic neoplasia
Inactivation of srnad4 accelerates KrasG12D-Mediated pancreatic neoplasia
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DOI：
10.1158/0008-5472.can-06-4167
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
King, Christopher A.
中科院分区：
文献类型：
--
作者：
Kojima, Kyoko;Vickers, Selwyn M.;King, Christopher A.
胰腺导管腺癌（PDAC）是人类最致命的恶性肿瘤之一，总体5年生存率<5%。PDAC患者样本的遗传分析表明，特定的疾病相关突变与导管上皮中肿瘤进展的组织学定义阶段相关。KRAS中的激活突变几乎一致地存在于早期疾病中，随后的p16（INK 4A）、p53和SAMD 4失活突变发生在更晚期的病变中。在这项研究中，我们已经测试了Smad 4的丢失是否会与激活Kras（G12 D）突变合作，以使用Pdvl-Cre转基因系统激活Kras（G12 D）并在包括导管上皮的所有胰腺谱系中删除Smad 4来促进向PDAC的进展。对双突变小鼠的分析表明，与Pdx 1-Cre;Kras（G12 D）或Pdx 1-Cre; Smad 4（lox/lox）小鼠相比，Smad 4缺失显著加速了胰腺上皮内瘤形成（mPanIN）的进展，并促进了导管内乳头状粘液性瘤形成和活动性纤维化的高发病率。偶尔，双突变小鼠进展为局部侵袭性PDAC，在6个月龄时几乎没有转移的证据，并且没有可检测到的p53或p16（Ink 4A）表达或功能的丧失。Smad 4的缺失似乎仅在存在活化的Kras（G12 D）等位基因的情况下促进疾病进展，因为我们在分析的23只Pdx 1-Cre; Smad 4（lox/lox）动物的胰腺内没有观察到异常病理学，这些动物长达8个月大。这表明Smad 4对于正常胰腺发育是必需的，但对于多种Kras（G12 D）依赖性疾病相关表型的至少部分抑制是关键的。
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of < 5%. Genetic analysis of PDAC patient samples has shown that specific disease-associated mutations are correlated with histologically defined stages of neoplastic progression in the ductal epithelium. Activating mutations in KRAS are almost uniformly present in early-stage disease, with subsequent inactivating mutations in p16(INK4A), p53, and SAMD4 occurring in more advanced lesions. In this study, we have tested whether the loss of Smad4 would cooperate with an activating Kras(G12D) mutation to promote progression to PDAC using the Pdvl-Cre transgenic system to activate Kras(G12D) and delete Smad4 in all pancreatic lineages including the ductal epithelium. Analysis of double-mutant mice showed that loss of Smad4 significantly accelerated the progression of pancreatic intraepithelial neoplasias (mPanIN) and promoted a high incidence of intraductal papillary mucinous neoplasia and active fibrosis compared with Pdx1-Cre;Kras(G12D) or Pdx1-Cre;Smad4(lox/lox) mice. Occasionally, double-mutant mice progressed to locally invasive PDAC with little evidence of metastases by 6 months of age and without the detectable loss of p53 or p16(Ink4A) expression or function. The loss of Smad4 only seemed to promote disease progression in the presence of the activated Kras(G12D) allele because we observed no abnormal pathology within the pancreata of 23 Pdx1-Cre;Smad4(lox/lox) animals that were analyzed up to 8 months of age. This indicates that Smad4 is dispensable for normal pancreatic development but is critical for at least partial suppression of multiple Kras(G12D)-dependent disease-associated phenotypes.