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Originally published as MBC in Press, 10.1091/mbc.E08-03-0283 on July 23, 2008

Vol. 19, Issue 10, 4110-4121, October 2008

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p120 and Kaiso Regulate Helicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Seth R. Ogden*, Lydia E. Wroblewski*, Christiane Weydig{dagger}, Judith Romero-Gallo*, Daniel P. O'Brien*, Dawn A. Israel*, Uma S. Krishna*, Barbara Fingleton*, Albert B. Reynolds*, Silja Wessler{dagger}, and Richard M. Peek, Jr*,{ddagger}

*Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2279; {dagger}Junior Research Group, Paul-Ehrlich Institute, D-63325, Langen, Germany; and {ddagger}Department of Veterans Affairs Medical Center, Nashville, TN 37212

Submitted March 14, 2008; Revised July 14, 2008; Accepted July 16, 2008
Monitoring Editor: Asma Nusrat

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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-03-0283) on July 23, 2008.

Address correspondence to: Richard M. Peek, Jr. (richard.peek{at}vanderbilt.edu)

Abbreviations used: cag, cytotoxin-associated gene; MMP-7, matrix metalloproteinase-7; p120, p120-catenin.




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