Abstract
RUNX3 (runt-related transcription factor-3) has been reported to suppress tumor tumorigenesis and metastasis in different human cancers. In this study, we used tissue microarray (TMA) to determine the significance of RUNX3 in prostate cancer progession. Our results showed ectopic expression of RUNX3 in prostate cancer tissues when compared with tumor adjacent normal prostate tissues, and reduced RUNX3 staining was significantly correlated with TNM stage. Moreover, we demonstrated that RUNX3 overexpression inhibited prostate cancer cell migration and invasion resulting from the elevated upregulation of tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), which subsequently inhibited metalloproteinase-2 (MMP-2) expression and activity in vitro. Knock down of RUNX3 expression broke up the balance of TIMP-2/MMP-2, whereas silence of TIMP-2 resulted in the inhibition of MMP-2 expression in prostate cells. We also showed that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation. Strikingly, RUNX3 was demonstrated to inhibit tumor metastasis and angiogenesis in vivo. Altogether, our results support the tumor suppressive role of RUNX3 in human prostate cancer, and provide insights into development of targeted therapy for this disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Animals
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Carcinoma / blood supply
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Carcinoma / genetics*
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Carcinoma / metabolism
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Carcinoma / secondary
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Cell Movement
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Core Binding Factor Alpha 3 Subunit / antagonists & inhibitors
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Core Binding Factor Alpha 3 Subunit / genetics*
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Core Binding Factor Alpha 3 Subunit / metabolism
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Disease Progression
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Gene Expression Regulation, Neoplastic*
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Lung Neoplasms / blood supply
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Male
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Mice
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Mice, Nude
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Middle Aged
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Neoplasm Invasiveness
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Neoplasm Staging
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Neoplasm Transplantation
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Neovascularization, Pathologic
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Prostatic Neoplasms / blood supply
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Tissue Array Analysis
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Tissue Inhibitor of Metalloproteinase-2 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Tumor Microenvironment
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Core Binding Factor Alpha 3 Subunit
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RNA, Small Interfering
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Runx3 protein, human
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TIMP2 protein, human
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Tissue Inhibitor of Metalloproteinase-2
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Matrix Metalloproteinase 2
Grants and funding
This project is supported by a grant from the National Natural Science Foundation of China (No. 81302207). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.