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.
Highlights
Prostate cancer is the second leading cause of cancer death among men in the USA [1]
RUNX3 Expression is Reduced in Human Prostate Cancer We first determined whether RUNX3 expression is changed in human prostate cancer
Previous reports have shown that RUNX3 expression was reduced in numerous types of human cancers, such as breast cancer, colorectal cancer, renal cell carcinoma, melanoma [8,11,13,18]
Summary
Prostate cancer is the second leading cause of cancer death among men in the USA [1]. Metastasis is an extraordinarily complex process, including cancer cells migrate out of primary tumors and invade into neighboring tissue, intravasate into the blood or the lymphatic circulation, survive in the blood stream, and target specific organs to initiate metastatic outgrowth [3]. Runt domain family, consisting of RUNX1, RUNX2, and RUNX3, are master regulators of gene expression in cell proliferation and differentiation. RUNX family proteins contain the well conserved domain with 128 amino-acids region (Runt domain) and form a stable complex with PEBP2b/CBFb to exert its transactivation ability [4]. RUNX proteins regulate the expression of cellular genes by binding to promoters or enhancers of target genes related to cell-fate decisions, which become deranged in cancer cells [6]
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