Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120ctn in pancreatic cancer

Abstract

Background and Aims: Cell adhesion proteins have been implicated as tumor suppressors because they prevent malignant cells from dissociating their cell contacts. We have studied the role of p120ctn, a recently discovered member of the cadherin/catenin family, in human pancreatic cancer. Methods: In 32 resection specimens of pancreatic adenocarcinoma and 10 control samples the expression of p120ctn was studied by Northern blot, immunocytochemistry, and immunogold electron microscopy. Patient survival data, tumor grading, and staging were correlated to the experimental results. In PaTu 8889 T pancreatic cancer cells, p120ctn expression was suppressed with 21-nucleotide small interfering RNA (siRNA) duplexes and proliferation was determined by bromodeoxyuridine (BrdU) incorporation. Results: In pancreatic cancer p120ctn messenger RNA (mRNA) was increased 3- to 4-fold. Although p120ctn was localized exclusively at cell contacts in controls it was found in the cytosol and nucleus of pancreatic cancer cells. This redistribution correlated to the degree of tumor dedifferentiation but was independent of tumor stage. The mean survival of patients with predominant membrane localization of p120ctn was 24 ± 7 (SEM) months vs. 9 ± 2 months for patients with predominant cytoplasmic p120ctn expression (P < 0.05). Silencing of p120ctn with siRNA duplexes reduced pancreatic cancer cell growth by 40%. Conclusions: Up-regulation, cytoplasmic redistribution, and nuclear import of p120ctn are associated with a more malignant phenotype of pancreatic cancer. This study further represents conclusive evidence for a direct involvement of p120ctn in malignant tumor cell proliferation. Both p120ctn-defective tumor cell contacts and p120ctn-mediated growth signals appear to contribute to the aggressive spread of pancreatic cancer.