Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1).
BACKGROUND
Metastasis-associated protein 1 (MTA1) is overexpressed in many forms of cancer types but its role in prostate cancer (PCa) progression and metastasis has not been explored. In this study, we addressed the functional and biological role of MTA1 in PCa.


METHODS
Gene expression profiling was used to determine MTA1 overexpression during PCa cell-bone interaction. Immunohistochemistry was used to detect MTA1 on tissue microarrays (TMA) and vascular endothelial growth factor (VEGF), CD31, and Ki67 in xenografts. We used retroviral or lentiviral RNAi transduction of PCa cells to establish MTA1 knockdowns. RT-PCR, Western blot, invasion, and endothelial cell migration assays were used to characterize the cells in vitro. The role of MTA1 in PCa tumorigenesis was evaluated in mouse xenografts.


RESULTS
We identified MTA1 as a component of bone metastasis signature in PCa, which suggested a possible role for MTA1 in PCa progression and metastasis. MTA1 was expressed at higher levels in PCa cell lines than in normal prostate epithelial cells. Silencing MTA1 significantly suppressed the invasion and angiogenic activity of the cells in vitro and delayed tumor formation and development in mouse xenografts. Tumors that express MTA1 had higher proliferative indices, secreted higher levels of VEGF and were more vascularized. Analysis of the human TMA showed positive correlation between MTA1 nuclear localization/staining intensity and PCa aggressiveness.


CONCLUSIONS
MTA1 pro-angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa.
Kai
Li
L
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Wang
Jun
J
Ivanovic
Marina
M
Chung
Yeon-Tae
YT
Laskin
William B
WB
Schulze-Hoepfner
Frank
F
Mirochnik
Yelena
Y
Satcher
Robert L
RL
Levenson
Anait S
AS
D000818:Animals; D002460:Cell Line; D006655:Histone Deacetylases / Q000032:analysis / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology; D012097:Repressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015534:Trans-Activators
C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases