Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer.

Abstract

Recently, we identified increased cathepsin X expression in H. pylori-infected gastric mucosa. Here, we describe further up-regulation in gastric cancer and report on the role of inflammatory cytokines required for cathepsin X up-regulation in H. pylori-infected gastric mucosa, as well as on consequences for cellular invasion. Biopsy specimens were taken from the antrum, corpus and cardia of H. pylori-infected and non-infected patients. Gastric cancer samples were obtained from patients undergoing gastric surgery. Cathepsin X was detected in gastric mucosa by quantitative real-time RT-PCR, western blotting and immunohistochemistry. Induction of cathepsin X expression in epithelial and inflammatory cells caused by H. pylori infection was tested in in vitro contact and non-contact co-cultures of AGS cells and monocytic cells. Patients with H. pylori gastritis showed significantly higher cathepsin X mRNA (2.5-fold) and protein (1.6-fold) expression than H. pylori-negative patients. Cathepsin X was also up-regulated in gastric cancer (3-12-fold) compared to non-neoplastic mucosa. Cathepsin X was predominantly expressed by macrophages in the mucosal stroma and in glands of the antral mucosa. In addition, tumour cells stained for cathepsin X in 26 (68%) patients with gastric carcinoma. In general, staining was significantly more common (20 vs. 6 patients) and more intense (3.55 vs. 0.83) in intestinal type gastric cancer than in the diffuse type. In vitro cell culture experiments revealed that intercellular signalling between pathogenicity island (PAI)-positive H. pylori-infected epithelial cells and macrophages via soluble factors in the culture medium seems to be responsible for increased expression of cathepsin X in monocytes. Using antisense oligonucleotides, cathepsin X up-regulation was directly associated with higher invasiveness in vitro. Although no correlation of cathepsin X expression and TNM stage was found, our study demonstrates that cathepsin X plays a role not only in the chronic inflammation of gastric mucosa but also in the tumourigenesis of gastric cancer.

• Authors: Sabine Krueger, Thomas Kalinski, Tanja Hundertmark, Thomas Wex, Dörthe Küster, Ulrich Peitz, Matthias Ebert, Dorit K Nägler, Udo Kellner, Peter Malfertheiner, Michael Naumann, Christoph Röcken, Albert Roessner
• Journal: The Journal of pathology (J Pathol) Vol. 207 Issue 1 Pg. 32-42 (Sep 2005) ISSN: 0022-3417 [Print] England
• PMID: 16025436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Cytokines
• RNA, Messenger
• RNA, Neoplasm
• Cathepsins
• CTSK protein, human
• Cathepsin K

Topics

• Adult
• Aged
• Cardia (enzymology)
• Cathepsin K
• Cathepsins (biosynthesis, genetics)
• Cytokines (pharmacology)
• Female
• Gastric Mucosa (enzymology)
• Gastritis (enzymology, microbiology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Helicobacter Infections (enzymology)
• Helicobacter pylori
• Humans
• Immunoenzyme Techniques
• Male
• Middle Aged
• Neoplasm Invasiveness
• Protein Array Analysis
• Pyloric Antrum (enzymology)
• RNA, Messenger (genetics)
• RNA, Neoplasm (genetics)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Stomach Neoplasms (enzymology, pathology)
• Stromal Cells (enzymology)
• Up-Regulation (drug effects)