The cytoplasmic enzyme dihydrodiol dehydrogenase (DDH) plays an important role in detoxification. Patients with DDH overexpression have a significantly higher incidence of early tumor recurrence and distant metastasis. This study evaluated the correlation between clinicopathological data and DDH expression and the prognostic significance of DDH expression in patients with resected gastric cancer. Between January 1998 and September 2004, we retrospectively enrolled 81 patients who received surgical treatment for gastric cancer. Pathology samples were immunostained with monoclonal antibody to DDH. The relationship between DDH expression and clinicopathological data (age, gender, histological type, stage) was analyzed by chi-square analysis. Survival curves were plotted using the Kaplan-Meier method and compared using a log-rank test. The overexpression rate of DDH was 41.9%. Of patients with overexpressed DDH, 13% had stage I, 24% had stage II, 52% had stage III, and 78% had stage IV tumors. Among patients who died, DDH expression level differed significantly between high and low-expression groups (P = 0.042). Survival was significantly better in patients with low DDH expression (P = 0.048). Thus, DDH expression may be useful in identifying high-risk gastric cancer patients and distinguishing future candidates for curative and palliative treatment.
Divalent lead ions (Pb(2+) ) are toxic environmental pollutants known to cause serious health problems in humans and animals. Absorption of Pb(2+) from air, water, and food takes place in the respiratory and digestive tracts. The ways in which absorbed Pb(2+) affects cell physiology are just beginning to be understood at the molecular level. Here, we used reverse transcription PCR and Western blotting to analyze cultures of human gastric carcinoma cells exposed to 10 μM lead nitrate. We found that Pb(2+) induces gastrin hormone gene transcription and translation in a time-dependent manner. Promoter deletion analysis revealed that activator protein 1 (AP1) was necessary for gastrin gene transcription in cells exposed to Pb(2+) . MitogIen-activated protein kinase (MAPK)/ERK kinase inhibitor PD98059 suppressed the Pb(2+) -induced increase in messenger RNA. Epidermal growth factor receptor (EGFR) inhibitors AG1478 and PD153035 reduced both transcription and phosphorylation by extracellular signal-regulated kinase (ERK1/2). Cells exposed to Pb(2+) also increased production of c-Jun protein, a component of AP1, and over-expression of c-Jun enhanced activation of the gastrin promoter. In sum, the findings suggest the EGFR-ERK1/2-AP1 pathway mediates the effects of Pb(2+) on gastrin gene activity in cell culture.
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