Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer.
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.
Krueger
Sabine
S
Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany. Sabine.Krueger@medizin.uni-magdeburg.de
Kalinski
Thomas
T
Hundertmark
Tanja
T
Wex
Thomas
T
Küster
Dörthe
D
Peitz
Ulrich
U
Ebert
Matthias
M
Nägler
Dorit K
DK
Kellner
Udo
U
Malfertheiner
Peter
P
Naumann
Michael
M
Röcken
Christoph
C
Roessner
Albert
A
D000328:Adult; D000368:Aged; D002299:Cardia / Q000201:enzymology; D056657:Cathepsin K; D002403:Cathepsins / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology; D005756:Gastritis / Q000201:enzymology* / Q000382:microbiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016481:Helicobacter Infections / Q000201:enzymology*; D016480:Helicobacter pylori; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D040081:Protein Array Analysis; D011706:Pyloric Antrum / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D017154:Stromal Cells / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K