Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Cancer Lett. 2014 Apr 28;346(1):104-13. doi: 10.1016/j.canlet.2013.12.021. Epub 2013 Dec 25.
The membrane mucin MUC4 is aberrantly expressed in multiple cancers and is of clinical significance to diagnosis and prognosis in pancreatic cancer. However, the role of MUC4 in angiogenesis and the potential association among these malignant capabilities have not been explored. In this study, we investigated the collective signaling mechanisms associated with MUC4-induced growth, metastasis and angiogenesis in pancreatic cancer. Knockdown of MUC4 in two pancreatic cancer cell lines led to downregulation of lysosomal degradation of E-cadherin by Src kinase through downregulation of pFAK and pSrc pathway. The downregulation of lysosomal degradation of E-cadherin in turn induced the formation of E-cadherin/β-catenin complex and membrane translocation of β-catenin, resulting in the downregulation of Wnt/β-catenin signaling pathway. Thus, the Wnt/β-catenin target genes c-Myc, Cyclin D1, CD44 and VEGF were down-regulated and their malignant functions proliferation, metastasis and angiogenesis were reduced. Taken together, MUC4-induced nuclear translocation of β-catenin is a novel mechanism for growth, metastasis and angiogenesis of pancreatic cancer.
膜黏蛋白 MUC4 在多种癌症中异常表达，对胰腺癌的诊断和预后具有临床意义。然而，MUC4 在血管生成中的作用以及这些恶性能力之间的潜在关联尚未得到探索。在这项研究中，我们研究了与胰腺癌细胞中 MUC4 诱导的生长、转移和血管生成相关的集体信号机制。在两种胰腺癌细胞系中敲低 MUC4 会导致 Src 激酶通过下调 pFAK 和 pSrc 途径下调 E-钙粘蛋白的溶酶体降解。E-钙粘蛋白的溶酶体降解下调反过来诱导 E-钙粘蛋白/β-连环蛋白复合物的形成和 β-连环蛋白的膜转位，从而下调 Wnt/β-连环蛋白信号通路。因此，Wnt/β-连环蛋白靶基因 c-Myc、Cyclin D1、CD44 和 VEGF 下调，其恶性功能增殖、转移和血管生成减少。总之，MUC4 诱导的β-连环蛋白核易位是胰腺癌生长、转移和血管生成的一种新机制。
