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Carcinogenesis Advance Access published online on March 10, 2005
Carcinogenesis, doi:10.1093/carcin/bgi045
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received October 2, 2004
Revised January 25, 2005
Accepted February 6, 2005

CARCINOGENESIS

Induction of DMBT1 expression by reduced ERK activity during gastric mucosa differentiation-like process and its association with human gastric cancer

Weiqun Kang 1, Ole Nielsen 2, Claus Fenger 2, R. Graham Q. Leslie 3, Uffe Holmskov 3, and Kenneth B. M. Reid 1*

1 MRC Immunochemistry Unit, Department of Biochemistry, Oxford University, Oxford, OX1 3QU, United Kingdom
2 Department of Pathology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark
3 Department of Immunology and Microbiology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark

* To whom correspondence should be addressed.
Kenneth B. M. Reid, E-mail: kenneth.reid{at}bioch.ox.ac.uk


  Abstract

Abnormalities in the expression of DMBT1 (deleted in malignant brain tumors 1) have been implicated in the development of esophageal, gastric and colorectal cancers of the alimentary tract, but the underlying mechanism remains unclear. In the present study using the gastric cell line AGS, we identified two intracellular signaling molecules PKC (protein kinase C) and ERK (extracellular signal-related kinase). They mediated both PMA downregulation of DMBT1 expression and the initiation of cell-differentiation, which was measured by cell cycle withdrawal and the induction of the tissue specific marker TFF1 (trefoil factor 1). A time-course study showed that following PMA activation of ERK kinase, the induction of TFF1 and the reduction of DMBT1 were detected at the same time point. We then demonstrated a minimal level of DMBT1 when ERK activity was high in proliferating AGS cells seeded at low density. Reduction of ERK activity, either by an ERK inhibitor PD98059 or by high density-seeding of AGS cells, significantly reduced cell growth judged by CFSE labeling. This cellular effect was elicited by cyclin D /p21 (Cip/Waf1) and G0/G1 arrest, and was accompanied by a marked increase in DMBT1-expressing cells. Finally, we showed that siRNA directed against DMBT1 had no effect on the induction of a cell growth arrest marker, GKLF (Gut-enriched Kruppel-like factor), but reduced PMA induction of TFF1. Together with its upregulation coinciding with G0/G1 arrest, and its attenuation in differentiated cells, these results suggest that the transient induction of DMBT1 is specific at an early stage of gastric epithelial differentiation-like process, when it may play a role in cell fate decision. Consistent with such a potential function, we detected frequent abnormalities of the DMBT1 expression in the specimens of human gastric adenocarcinoma.

Keywords: DMBT1; ERK; Gastric epithelia; Differentiation; Gastric adenocarcinoma.
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