Journal Article

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

Weiqun Kang, Ole Nielsen, Claus Fenger, Graham Leslie, Uffe Holmskov and Kenneth B.M. Reid

in Carcinogenesis

Volume 26, issue 6, pages 1129-1137
Published in print June 2005 | ISSN: 0143-3334
Published online March 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi045
Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer

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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 protein kinase C (PKC) and extracellular signal-related kinase (ERK). They mediated both the phorbol myristate acetate (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 trefoil factor 1 (TFF1). A time-course study showed that following the 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 in proliferating AGS cells seeded at low density, where ERK activity was high. Reduction of ERK activity, either by an ERK inhibitor PD98059 or by high-density seeding, significantly reduced AGS 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, gut-enriched Kruppel-like factor (GKLF), but reduced the PMA induction of TFF1. Along with its upregulation coinciding with G0/G1 arrest, and its attenuation in differentiated cells, these results suggest that the transient induction of DMBT1 is apparently 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: CFSE, 5-,6-carboxyfluorescein diacetate succinimidyl ester; DMBT1, deleted in malignant brain tumors 1; DMSO, dimethyl sulfoxide; ERK, extracellular signal-related kinase; GKLF, gut-enriched Kruppel-like factor; MEK, MAP kinase kinase; mAbs, monoclonal antibodies; PBS, phosphate-buffered saline; PMA, phorbol myristate acetate; PKC, protein kinase C; PI, propidium iodide; RT–PCR, reverse transcriptase–polymerase chain reaction; TFF1, trefoil factor 1; TfR, transferring receptor

Journal Article.  6333 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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