Studies on MUC1, p120 catenin, Kaiso: Coordinate role of mucins, cell adhesion molecules and cell cycle players in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA), commonly referred to as pancreatic cancer, is one of the devastating diseases that cause a high death rate worldwide. Pancreatic cancer develops as a consequence of the accumulation of genetic alterations that activate oncogenes and inactivate tumor-suppressor genes. During the process of disease progression, pancreatic carcinoma initiates from early pancreatic intraepithelial neoplasia lesions that progress to aggressive local invasion of adjacent structures, nerves, lymph nodes and finally metastasis to the liver and other organs. Recently, scientists have elucidated the molecular mechanisms of several aberrant signaling pathways that contribute to the initiation and progression of pancreatic cancer. However, to better understand the metastatic behavior of this invasive carcinoma, we need to dissect the molecular mechanisms that regulate four fundamental biological processes: cell polarity, adhesion, migration and proliferation. Our studies examine the MUCI.CT/Beta-catenin/TCP-LEF/p120-catenin/Kaiso pathway in the development and progression of pancreatic cancer. The WNT signaling pathway plays a major role in cell growth and differentiation during embryogenesis.Alterations in this pathway are known to affect pancreatic adenocarcinoma tumor cells. We hypothesized that MUC1 modulated proliferative properties of tumor cells through effects on the p120 ctnfKaiso/Beta-cateninlTCF-LEF signaling pathway. Our results suggest that MUC1 disrupted interactions between E-cadherin and p120 ctn, and beta-ctn. Following p120 ctn and beta-ctn release from E-cadherin, beta-catenin localized to the nucleus, was bound to TCF/Lef and activated WNT target genes. Interactions between p120 and Kaiso relieved transcriptional repression of WNT target gene transcription, including genes that regulated cell proliferation and invasion. Activation of TCF/ LEF by beta-catenin in combination with p120-mediated de-repression of the Kaiso transcriptional repressor hyperactivated WNT target gene expression. We further showed that p120-catenin ARM domains 1, 3-5 and 8 mediate interactions between p120-catenin and MUC1, and that these interactions modulate dynamic properties of cell adhesion, motility and metastasis of pancreatic cancer cells. We found that different isoforms of p120-catenin, when co-expressed with MUC1, create cells that exhibit distinct patterns of motility in culture (motility independent of cell adhesion, motility within a monolayer while exchanging contacts with other cells, and unified motility while maintaining static epithelial contacts) and patterns of metastasis. In summary, our research provides novel insights into multiple aspects of molecular mechanisms whereby MUC1, p120-catenin and Kaiso modulate cell proliferation, cell adhesion and cell invasion properties of pancreatic cancer cells.