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Published on: February 21, 2014
Downregulation of estrogen-metabolizing 17 beta-hydroxysteroid dehydrogenase type 2 expression correlates inversely
Olayiwola O Oduwole1, Veli V Isomaa, Pasi A Nokelainen
1Biocenter Oulu, WHO Collaborating Centre for Research on Reproductive Health, University of Oulu, Oulu, Finland.
Abstract:
The 17HSDs are a group of isozymes that catalyze the interconversion between high-activity 17 beta-hydroxysteroids and low-activity 17-ketosteroids. In the present study, we characterized the expression of 17HSD types 1 and 2 in normal and malignant gastrointestinal tissues and cells. Using the colon as a model for cancer of the gastrointestinal tract, expression of the 17HSD enzymes in cancer development was studied and correlated with proliferation and differentiation markers as assessed by Ki67 and mucin staining, respectively. In normal colon and small intestine, 17HSD type 2 mRNA was expressed in the surface epithelial cells and, to a lesser extent, in the cryptal epithelial cells. In colon-cancer specimens, 17HSD type 2 expression was downregulated both in the tissues and in the cell lines and correlated inversely with the proliferation marker. No expression for the 17HSD type 1 enzyme was observed in normal or cancerous gastrointestinal tract tissues. In line with the expression studies, 17HSD activity measurements with colon cells showed that only the oxidative conversion of E2 to E1 was present, and Northern blot analysis showed the signal only for 17HSD type 2. Localization of the ERs alpha and beta, assessed by immunohistochemistry and in situ hybridization, showed the presence of ER beta in the lamina propria of the colon. Our study shows that 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. The decrease in expression of the type 2 enzyme may increase estrogen influence in colon cancer.
Insights
17-hydroxysteroid dehydrogenases (17HSDs) are key enzymes in steroid metabolism. This study found that reduced 17HSD type 2 expression in colon cancer correlates with increased proliferation, suggesting a role for estrogen in cancer development.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- 17-hydroxysteroid dehydrogenases (17HSDs) interconvert active 17 beta-hydroxysteroids and inactive 17-ketosteroids.
- Understanding 17HSD expression is crucial for comprehending steroid hormone regulation in normal and malignant tissues.
Purpose of the Study:
- To characterize the expression and function of 17HSD types 1 and 2 in gastrointestinal tissues and cells.
- To investigate the role of 17HSD enzymes in colon cancer development and their correlation with proliferation and differentiation markers.
Main Methods:
- Quantitative analysis of 17HSD type 1 and 2 mRNA and protein expression in normal and cancerous gastrointestinal tissues and cell lines.
- Enzyme activity assays to measure steroid interconversion.
- Immunohistochemistry and in situ hybridization to determine the localization of estrogen receptors (ERs).
- Correlation analysis with proliferation (Ki67) and differentiation (mucin) markers.
Main Results:
- 17HSD type 2 mRNA was detected in normal colon and small intestine epithelial cells, but its expression was significantly downregulated in colon cancer tissues and cell lines.
- 17HSD type 1 expression was not observed in any gastrointestinal tissues.
- Downregulation of 17HSD type 2 in colon cancer correlated inversely with Ki67 proliferation marker.
- Colon cells exhibited oxidative 17HSD activity (E2 to E1 conversion), consistent with 17HSD type 2 presence.
- ER beta was localized in the lamina propria of the colon.
Conclusions:
- 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract.
- Decreased 17HSD type 2 expression in colon cancer may lead to increased local estrogen influence, potentially promoting cancer progression.
- Targeting 17HSD type 2 could be a therapeutic strategy for colon cancer.
