Platelets express steroidogenic 17β–hydroxysteroid dehydrogenases

Abstract

Human blood platelets have important, regulatory functions in diverse hemostatic and pathological disorders, including vascular remodeling, inflammation, and wound repair. Microarray analysis was used to study the molecular basis of essential thrombocythemia, a myeloproliferative disorder with quantitative and qualitative platelet defects associated with cardiovascular and thrombohemorrhagic symptoms, not infrequently neurological. A platelet-expressed gene (HSD17B3) encoding type 3 17beta-hydroxysteroid dehydrogenase (previously characterized as a testis-specific enzyme catalyzing the final step in gonadal synthesis of testosterone) was selectively down-regulated in ET platelets, with reciprocal induction of the type 12 enzyme (HSD17B12). Functional 17beta-HSD3 activity corresponding to approximately 10% of that found in murine testis was demonstrated in normal platelets. The induction of HSD17B12 in ET platelets was unassociated with a concomitant increase in androgen biosynthesis, suggesting distinct functions and/or substrate specificities of the types 3 and 12 enzymes. Application of a molecular assay distinguished ET from normal platelets in 20 consecutive patients (p < 0.0001). These data provide the first evidence that distinct subtypes of steroidogenic 17beta-HSDs are functionally present in human blood platelets, and that the expression patterns of HSD17B3 and HSD17B12 are associated with an uncommon platelet disorder manifest by quantitative and qualitative platelet defects.

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

“…Microarray and subsequent RT-PCR and functional analysis indicated that 17b-HSD3, along with 17b-HSD12, is also expressed in human blood platelets and megakaryocytes. While 17b-HSD12 is up-regulated O25-fold in essential thrombocythemia, a rare myeloproliferative disorder, 17b-HSD3 is down-regulated w4.5-fold (Gnatenko et al 2005).…”

Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms

“…Microarray mRNA profiles included our previously described 6 ET subjects and 5 healthy controls (GEO accession no. GPL1716) 22 ; a filtering step was applied to retain genes expressed in at least 6 samples, and genes represented by duplicate probes were combined and averaged before quantile normalization. For proteomics data, quantile-normalized MS spectral counts were averaged by cohort, restricting the analyses to proteins displaying spectral counts Ͼ 10 to bypass the inherent limitations of protein quantification at low spectral counts.…”

“…Given the limitations of miRNA target identification using computational databases, 27 we systematically dissected the effects of dysregulated miRNA 490 expressions by incorporating a workflow model linking miRNA, mRNA, and proteomic expression patterns in normal and thrombocytotic states ( Figure 5A). We used previously described mRNA genetic profiles from 6 ET patients and 5 healthy controls, 22 and spectral (peptide) counts generated by multidimensional protein identification technology (MudPIT) 20 as a semiquantitative means of platelet protein estimation, using samples from 3 healthy controls and 3 ET subjects. If miRNA 490 modulates protein expression, 2 distinct patterns would be expected: (1) inverse relationship of the miRNA and mRNA/ protein pair (ie, a mRNA degradation pathway), or (2) inverse relationship of miRNA and protein without affecting mRNA (ie, translation repression).…”

STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

“…Although 17b-HSD3 is expressed almost exclusively in testis microsomes (Geissler et al 1994, Luu-The et al 1995, there have been some reports of its expression in other tissues, such as blood platelets and megakaryocytes (Gnatenko et al 2005), and its up-regulation in tumours of the prostate. Expression of 17b-HSD3 mRNA increased over 30-fold in prostate tumour biopsies in one report (Koh et al 2002), with a corresponding decrease in 17b-HSD2 mRNA expression, indicating that the reductive formation of testosterone is favoured, and was up-regulated in an AR-positive prostate cell line, LNCaP, after a 48-h treatment with dutasteride (Biancolella et al 2007), a 5a-reductase 1 and 2 inhibitor.…”