Cooperativity of E-cadherin and Smad4 loss to promote diffuse-type gastric adenocarcinoma and metastasis.
Cooperativity of E-cadherin and Smad4 loss to promote diffuse-type gastric adenocarcinoma and metastasis.
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DOI：
10.1158/1541-7786.mcr-14-0192-t
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Kim HK
中科院分区：
文献类型：
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作者：
Park JW;Jang SH;Park DM;Lim NJ;Deng C;Kim DY;Green JE;Kim HK
E-cadherin （CDH1）、Smad4和p53的缺失都被证明在胃癌、肠癌和乳腺癌的形成中起着不可或缺的作用。通过与Pdx-1-Cre、Villin-Cre和MMTV-Cre转基因小鼠杂交，生成Smad4、p53和E-cadherin复合条件敲除小鼠，确定并比较这些基因在胃癌、肠癌和乳腺癌发展中的作用。有趣的是，胃腺癌在Pdx-1-Cre、Smad4F/F、Trp53F/F；cd1f /+小鼠比Pdx-1-Cre、Smad4F/F、Trp53F/F；Cdh1+/+小鼠，表明Cdh1杂合性与Smad4和p53的缺失一起加速了胃腺癌的发生和进展。Pdx-1-Cre; Smad4F / F; Trp53F / F;无E-cadherin表达的Cdh1F/+小鼠发生胃腺癌。然而，具有相同遗传背景的肠和乳腺腺癌保留了E-cadherin表达，并且在表型上与具有两种野生型Cdh1等位基因的小鼠相似。肺转移灶分别为：Pdx-1-Cre、Smad4F/F、Trp53F/F；Cdh1F/+小鼠，但在其他基因型中没有。核β-连环蛋白积累在胃腺癌的侵袭性肿瘤前部，发生在Pdx-1-Cre、Smad4F/F、Trp53F/F；Cdh1F / +老鼠。这种表型在完整的E-cadherin或Smad4小鼠中不太明显，表明E-cadherin或Smad4抑制β-catenin信号传导下调了Pdx-1-Cre、Smad4F/F、Trp53F/F、Smad4F和Smad4参与转移的信号通路。Cdh1F / +老鼠。敲低β-catenin可显著抑制Pdx-1-Cre、Smad4F/F、Trp53F/F；Cdh1F/+细胞系。因此，E-cadherin和Smad4的缺失与p53的缺失协同促进胃腺癌的发生和转移进展，与人胃腺癌相似。本研究表明，β-catenin的抑制是E-cadherin和Smad4驱动的Pdx-1-Cre、Smad4F/F、Trp53F/F和Smad4驱动的抗转移信号通路的汇聚节点。Cdh1F/+小鼠，为胃癌转移机制提供了新的见解。
Loss of E-cadherin (CDH1), Smad4 and p53 have all been shown to play an integral role in gastric, intestinal and breast cancer formation. Compound conditional knockout mice for Smad4, p53, and E-cadherin were generated to define and compare the roles of these genes in gastric, intestinal and breast cancer development by crossing with Pdx-1-Cre, Villin-Cre and MMTV-Cre transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1+/+ mice, demonstrating that Cdh1 heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas without E-cadherin expression. However, intestinal and mammary adenocarcinomas with the same genetic background retained E-cadherin expression and were phenotypically similar to mice with both wild-type Cdh1 alleles. Lung metastases were identified in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. Nuclear β-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of β-catenin signaling by E-cadherin or Smad4 down-regulates signaling pathways involved in metastases in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Knockdown of β-catenin significantly inhibited migratory activity of Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ cell lines. Thus, loss of E-cadherin and Smad4 cooperate with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma. This study demonstrates that inhibition of β-catenin is a converging node for the anti-metastatic signaling pathways driven by E-cadherin and Smad4 in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, providing novel insights into mechanisms for gastric cancer metastasis.