Regulation of cell proliferation through a KIT-mediated mechanism in benign prostatic hyperplasia.
BACKGROUND
We investigated the role of the KIT-mediated mechanism in benign prostatic hyperplasia (BPH), and discuss the pathophysiology of BPH and a candidate target of BPH medical therapy.


METHODS
We performed RT-PCR, Western blotting, and immunohistochemistry to examine the expression of KIT in the prostate using a human prostate stromal cell line (PrSC) and human prostate. To investigate the pathophysiological function of KIT, the effects of KIT ligand, stem cell factor (SCF), and imatinib mesylate on cell proliferation were investigated using PrSC. Additionally, we compared the expression level and distribution of KIT in normal prostate and BPH of humans to clarify the contribution of KIT to the pathogenesis of BPH.


RESULTS
KIT was expressed in PrSC and human prostate, indicating that these samples are suitable for examining the function of KIT. Immunohistochemical analysis demonstrated that KIT was localized in interstitial cells (ICs) of the stromal component in human prostate. Administration of imatinib mesylate dose-dependently inhibited cell proliferation of PrSC with downregulation of JAK2 and STAT1, which are the main pathways downstream of SCF/KIT signal. SCF promoted cell proliferation of PrSC with upregulation of JAK2 and STAT1. KIT expression and the number of KIT-positive ICs in BPH were found to be significantly larger than in normal prostate.


CONCLUSIONS
This is the first report to suggest that KIT regulates cell proliferation in the prostate and plays a significant role in the pathophysiology of BPH. Our study may lead to a greater understanding of the mechanism of BPH and provide a therapeutic target.
Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
Makoto
M
Imura
Yoshiyuki
Y
Kojima
Yasue
Y
Kubota
Takashi
T
Hamakawa
Takahiro
T
Yasui
Shoichi
S
Sasaki
Yutaro
Y
Hayashi
Kenjiro
K
Kohri
D000368:Aged; D001549:Benzamides; D015153:Blotting, Western; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011470:Prostatic Hyperplasia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D019089:Stem Cell Factor / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C507924:JAK2 protein, human; D053614:Janus Kinase 2