Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer.

Abstract

BACKGROUND & 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 p120(ctn), 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 p120(ctn) 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, p120(ctn) expression was suppressed with 21-nucleotide small interfering RNA (siRNA) duplexes and proliferation was determined by bromodeoxyuridine (BrdU) incorporation.

RESULTS:

In pancreatic cancer p120(ctn) messenger RNA (mRNA) was increased 3- to 4-fold. Although p120(ctn) 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 p120(ctn) was 24 +/- 7 (SEM) months vs. 9 +/- 2 months for patients with predominant cytoplasmic p120(ctn) expression (P < 0.05). Silencing of p120(ctn) with siRNA duplexes reduced pancreatic cancer cell growth by 40%.

CONCLUSIONS:

Up-regulation, cytoplasmic redistribution, and nuclear import of p120(ctn) are associated with a more malignant phenotype of pancreatic cancer. This study further represents conclusive evidence for a direct involvement of p120(ctn) in malignant tumor cell proliferation. Both p120(ctn)-defective tumor cell contacts and p120(ctn)-mediated growth signals appear to contribute to the aggressive spread of pancreatic cancer.

• Authors: Julia Mayerle, Helmut Friess, Markus W Büchler, Jürgen Schnekenburger, Frank U Weiss, Klaus-P Zimmer, Wolfram Domschke, Markus M Lerch
• Journal: Gastroenterology (Gastroenterology) Vol. 124 Issue 4 Pg. 949-60 (Apr 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12671892 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catenins
• Cell Adhesion Molecules
• Phosphoproteins
• RNA, Messenger
• RNA, Small Interfering
• Delta Catenin
• CTNND1 protein, human

Topics

• Active Transport, Cell Nucleus
• Adenocarcinoma (mortality, pathology, physiopathology)
• Adherens Junctions (metabolism, ultrastructure)
• Aged
• Blotting, Northern
• Catenins
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Division
• Cell Membrane (metabolism, ultrastructure)
• Cell Nucleus (metabolism, ultrastructure)
• Cytosol (metabolism, ultrastructure)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Immunohistochemistry
• Microscopy, Electron
• Middle Aged
• Pancreatic Neoplasms (mortality, pathology, physiopathology)
• Phosphoproteins (genetics, metabolism)
• RNA, Messenger (analysis)
• RNA, Small Interfering
• Survival Analysis
• Up-Regulation
• Delta Catenin