Smits R, Ruiz P, Diaz-Cano S, Luz A, Jagmohan-Changur S, Breukel C, Birchmeier C, Birchmeier W, Fodde R
Medical Genetics Center, Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Gastroenterology. 2000 Oct;119(4):1045-53. doi: 10.1053/gast.2000.18162.
BACKGROUND & AIMS: Inactivation of the adenomatous polyposis coli (APC) gene is observed at early stages of intestinal tumor formation, whereas loss of E-cadherin is usually associated with tumor progression. Because both proteins compete for the binding to beta-catenin, an essential component of the Wnt signaling pathway, reduction of E-cadherin levels in an Apc mouse model could influence both tumor initiation and progression. In addition, loss or haploinsufficiency of E-cadherin may affect tumorigenesis by altering its cell-adhesive and associated functions.
Apc1638N mice were bred with animals carrying a targeted E-cadherin knockout mutation.
Double heterozygous animals showed a significant 9-fold and 5-fold increase of intestinal and gastric tumor numbers, respectively, compared with Apc1638N animals. The intestinal tumors of both groups showed no significant differences in grading and staging. Loss of heterozygosity analysis at the Apc and E-cadherin loci in both intestinal and gastric Apc(+/1638N)/E-cad(+/-) tumors revealed loss of the wild-type Apc allele in most cases, whereas the wild-type E-cadherin allele was always retained. This was supported by a positive, although reduced, staining for E-cadherin of intestinal tumor sections.
Introduction of the E-cadherin mutation in Apc1638N animals enhances Apc-driven tumor initiation without clearly affecting tumor progression.
在肠道肿瘤形成的早期阶段可观察到腺瘤性息肉病大肠杆菌（APC）基因失活，而E-钙黏蛋白的缺失通常与肿瘤进展相关。由于这两种蛋白都竞争与β-连环蛋白（Wnt信号通路的重要组成部分）的结合，在Apc小鼠模型中降低E-钙黏蛋白水平可能会影响肿瘤的起始和进展。此外，E-钙黏蛋白的缺失或单倍剂量不足可能通过改变其细胞黏附及相关功能来影响肿瘤发生。
将Apc1638N小鼠与携带靶向E-钙黏蛋白敲除突变的动物进行杂交。
与Apc1638N动物相比，双杂合动物的肠道和胃肿瘤数量分别显著增加了9倍和5倍。两组的肠道肿瘤在分级和分期上无显著差异。对肠道和胃的Apc(+/1638N)/E-cad(+/-)肿瘤中Apc和E-钙黏蛋白位点的杂合性缺失分析显示，在大多数情况下野生型Apc等位基因缺失，而野生型E-钙黏蛋白等位基因总是保留。肠道肿瘤切片中E-钙黏蛋白染色呈阳性（尽管减弱），这支持了上述结果。
在Apc1638N动物中引入E-钙黏蛋白突变可增强Apc驱动的肿瘤起始，而不会明显影响肿瘤进展。
