Down-regulation of macrophage inhibitory cytokine-1/prostate derived factor in benign prostatic hyperplasia.
BACKGROUND
Macrophage inhibitory cytokine-1 (MIC-1) is a member of transforming growth factor-beta/bone morphogenetic protein (BMP) superfamily. Despite its potential role in prostatic regulation, little is known about its biological activity.


METHODS
Expression profiling using 42K Affymetrix HuGeneFL array was conducted to compare symptomatic benign prostatatic hyperplasia (BPH), histological BPH without symptoms, and normal prostate samples from donors. MIC-1 gene expression was analyzed by RT-PCR in pure culture of prostate epithelial and stromal cells, and prostate cancer cells, LNCaP, PC-3, DU-145. Influence of androgens on MIC-1 expression in LNCaP cells was analyzed by Northern blot. Enhancement of promoter activity of MIC-1 by androgens was examined using reporter assays.


RESULTS
In contrast to normal prostates, MIC-1 gene was down-regulated in BPH samples with symptoms and histological BPH obtained from cystoprostatectomy specimens (P < 0.005 and P < 0.01, respectively). Expression level of MIC-1 in androgen-sensitive LNCaP cells was high and enhanced by androgens, whereas in the androgen-insensitive PC-3 and DU-145 cells the expression level was low. An 11 kb promoter region of MIC-1 gene was identified to be 6- to 12-fold activated by androgens.


CONCLUSIONS
Down-regulation of MIC-1 may play a role in the development of BPH. MIC-1 is positively regulated by androgens, but other regulatory factors remain unclear.
Kakehi
Yoshiyuki
Y
Department of Urology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan. kakehi@kms.ac.jp
Segawa
Takehiko
T
Wu
Xiu-Xian
XX
Kulkarni
Prakash
P
Dhir
Rajiv
R
Getzenberg
Robert H
RH
D000328:Adult; D019485:Bone Morphogenetic Proteins; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D011467:Prostate / Q000502:physiology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D008565:Membrane Proteins