Dysregulation of Dkk-3 expression in benign and malignant prostatic tissue.
BACKGROUND
The Dickkopf (Dkk) family comprises four members Dkk-1, -2, -3, and -4. Dkk-3, the most divergent family member, unlike the others does not modulate Wnt signaling. Dkk-3 is proposed to function as a secreted tumor suppressor since it is downregulated in a number of cancer cells and prostate cancer tissue and thus may be a promising candidate molecule for therapeutic interference.


METHODS
The in situ tissue localization of Dkk-3 protein in normal prostate (NP), benign prostatic hyperplasia (BPH), and prostate carcinoma (PCa) was investigated by immunohistochemistry (IHC)/immunofluorescence. In addition, biological function of Dkk-3 in terms of proliferation and viability was evaluated in primary prostate basal epithelial cells (PrEC), stromal cells (PrSC), and established human PCa cell lines by treatment with recombinant protein or by overexpression.


RESULTS
Stimulation with purified recombinant protein and overexpression of Dkk-3 did not significantly alter in vitro cell proliferation in any primary or tumor cell line evaluated. Dkk-3 was expressed in both the basal and secretory epithelium of NP. In BPH expression was restricted to defined basal cells and was absent in tumor cells of high grade PCa. In contrast to normal prostatic tissue, Dkk-3 was upregulated in subglandular blood vessels of BPH and in the reactive stroma of PCa tissue.


CONCLUSIONS
Our results indicate that Dkk-3 expression in the normal epithelium of the prostate is lost during benign and malignant transformation and differentiation processes. The loss of expression seems to be counterbalanced by upregulation of Dkk-3 expression in the blood vessels of the remodeled tissue.
Zenzmaier
Christoph
C
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Untergasser
Gerold
G
Hermann
Martin
M
Dirnhofer
Stephan
S
Sampson
Natalie
N
Berger
Peter
P
D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018925:Chemokines; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins