Nuclear factor-kappaB-mediated transforming growth factor-beta-induced expression of vimentin is an independent predictor of biochemical recurrence after radical prostatectomy.
OBJECTIVE
Transforming growth factor-beta (TGF-beta)-mediated epithelial-to-mesenchymal transition (EMT) has been shown to occur in some cancers; however, the pathway remains controversial and varies with different cancers. In addition, the mechanisms by which TGF-beta and the EMT contribute to prostate cancer recurrence are largely unknown. In this study, we elucidated TGF-beta-mediated EMT as a predictor of disease recurrence after therapy for prostate cancer, which has not been reported before.


METHODS
We analyzed TGF-beta-induced EMT using nuclear factor-kappaB (NF-kappaB) as an intermediate mediator in prostate cancer cell lines. A total of 287 radical prostatectomy specimens were evaluated using immunohistochemistry in a high-throughput tissue microarray analysis. Levels of TGF-beta signaling components and EMT-related factors were analyzed using specific antibodies. Results were expressed as the percentage of cancer cells that stained positive for a given antibody and were correlated with disease recurrence rates at a mean of 7 years following radical prostatectomy.


RESULTS
In prostate cancer cell lines, TGF-beta-induced EMT was mediated by NF-kappaB signaling. Blockade of NF-kappaB or TGF-beta signaling resulted in abrogation of vimentin expression and inhibition of the invasive capability of these cells. There was high risk of biochemical recurrence associated with tumors that displayed high levels of expression of TGF-beta1, vimentin, and NF-kappaB and low level of cytokeratin 18. This was particularly true for vimentin, which is independent of patients' Gleason score.


CONCLUSIONS
The detection of NF-kappaB-mediated TGF-beta-induced EMT in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-beta signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment.
Zhang
Qiang
Q
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. q-zhang2@northwestern.edu .
Helfand
Brian T
BT
Jang
Thomas L
TL
Zhu
Lihua J
LJ
Chen
Lin
L
Yang
Ximing J
XJ
Kozlowski
James
J
Smith
Norm
N
Kundu
Shilajit D
SD
Yang
Guangyu
G
Raji
Adekunle A
AA
Javonovic
Borko
B
Pins
Michael
M
Lindholm
Paul
P
Guo
Yinglu
Y
Catalona
William J
WJ
Lee
Chung
C
D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004848:Epithelium / Q000737:chemistry / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000737:chemistry / Q000473:pathology; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014746:Vimentin / Q000378:metabolism*
D053538:Keratin-18; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D014746:Vimentin