p120 and Kaiso regulate Helicobacter pylori-induced expression of matrix metalloproteinase-7.
Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons develop cancer. One H. pylori constituent that augments disease risk is the cytotoxin-associated gene (cag) pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Matrix metalloproteinase (MMP)-7, a member of a family of enzymes with tumor-initiating properties, is overexpressed in premalignant and malignant gastric lesions, and H. pylori cag(+) strains selectively increase MMP-7 protein levels in gastric epithelial cells in vitro and in vivo. We now report that H. pylori-mediated mmp-7 induction is transcriptionally regulated via aberrant activation of p120-catenin (p120), a component of adherens junctions. H. pylori increases mmp-7 mRNA levels in a cag- and p120-dependent manner and induces translocation of p120 to the nucleus in vitro and in a novel ex vivo gastric gland culture system. Nuclear translocation of p120 in response to H. pylori relieves Kaiso-mediated transcriptional repression of mmp-7, which is implicated in tumorigenesis. These results indicate that selective and coordinated induction of mmp-7 expression by H. pylori cag(+) isolates may explain in part the augmentation in gastric cancer risk associated with these strains.
Ogden
Seth R
SR
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2279, USA.
Wroblewski
Lydia E
LE
Weydig
Christiane
C
Romero-Gallo
Judith
J
O'Brien
Daniel P
DP
Israel
Dawn A
DA
Krishna
Uma S
US
Fingleton
Barbara
B
Reynolds
Albert B
AB
Wessler
Silja
S
Peek
Richard M
RM
D021581:Active Transport, Cell Nucleus; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013274:Stomach Neoplasms / Q000382:microbiology* / Q000473:pathology; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000095002:Delta Catenin
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D051177:Catenins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; C492254:ZBTB33 protein, human; C080866:cagA protein, Helicobacter pylori; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D000095002:Delta Catenin