Characterization of 17B‐hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate

Abstract

In the present study, expressions of 17beta-hydroxysteroid dehydrogenase (17HSD) types 1, 2, and 3, 5alpha-reductase type 2 and human androgen receptor mRNAs were determined in 12 benign prostatic hyperplasia and 17 prostatic carcinoma specimens. 17HSD type 2 was found to be the principle isoenzyme expressed in the prostate. Significantly higher expressions of 17HSD type 2 and 5alpha-reductase type 2 were detected in benign prostatic hyperplasia compared with the carcinoma specimens. Expression of the androgen receptor in the 2 groups was not significantly different. 17HSD type 3 mRNA was not detected in any of the specimens investigated. Only low constructive expression of the 2.3 kb mRNA of 17HSD type 1 was seen. Immunohistochemical analysis indicated that this did not lead to significant enzyme expression, only faint staining for the enzyme protein being detected, mainly in uroepithelial cells. No significant correlation was found between any of the mRNAs analysed, but the data on 5alpha-reductase type 2 mRNA support the presence of an increased proportion of 5alpha-dihydrotesterone in the hyperplastic prostate. In cultured PC-3 prostatic cancer cells and in the transiently transfected human embryonic kidney 293 cells, 17HSD type 2 was found exclusively to convert 5alpha-dihydrotestosterone and testosterone into the less potent 17-keto compounds 5alpha-androstanedione and 4-androstenedione, respectively. We suggest that the 17HSD type 2 isoenzyme plays a part in the metabolic pathway, resulting in the inactivation of testosterone and 5alpha-dihydrotestosterone locally in the prostate. The enzyme expressed in the prostate could, therefore, protect cells from excessive androgen action.

Sex steroid hormone metabolism and prostate cancer

“…It was suggested that potent product inhibition by NADPH and oxidation of 3␣A-diol to androsterone by 17HSD type 2 are possible reasons for the lack of DHT formation in the cells studied. Testosterone and DHT are mainly inactivated in the prostate by 17HSD type 2 to A-dione and 5␣-androstanedione (5␣A-dione), respectively [16]. DHT can also be reduced into 3␣A-diol by 3␣-HSD type 3 [14] or an estrogenic compound 5␣-androstane-3␤,17␤-diol (3␤A-diol) by 3␤-HSD [14] or 17HSD type 7 [17].…”

Regulation of 17β-hydroxysteroid dehydrogenase type 2, type 4 and type 5 by calcitriol, LXR agonist and 5α-dihydrotestosterone in human prostate cancer cells

“…Interestingly, an association of the loss of heterozygosity at HSD17B2 gene containing chromosomal region, 16q24.1-16q24.2, and a risk for clinically aggressive prostate cancer has been reported [2,10,11]. The expression level of HSD17B2 is significantly higher in benign prostatic hyperplasia compared with the carcinoma specimens [12]. Vitamin D deficiency is a risk factor for prostate cancer mortality [13][14][15].…”

Functional genome analysis indicates loss of 17beta-hydroxysteroid dehydrogenase type 2 enzyme in the zebrafish

“…Furthermore, the enzyme exhibits 20alpha-hydroxysteroid dehydrogenase activity toward 20alpha-dehydroprogesterone [4]. Expression of the enzyme is not very restricted but has been found in a variety of human [6][7][8][9][10] as well as mouse [11,12] tissues. The wide-spread occurrence together with the catalyzed reaction of testosterone and estradiol oxidation has lead to the suggestion that the biological function of 17beta-HSD 2 is maintenance of the delicate balance of active and non-active androgens and estrogens in target tissues and the protection of non-target tissues from these potent sex hormones.…”