Chen Feifei, Wang Meng, Bai Jin, Liu Qinghua, Xi Yaguang, Li Wang, Zheng Junnian
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu, China.
School of Pathology, Xuzhou Medical College, Xuzhou, Jiangsu, China.
PLoS One. 2014 Jan 24;9(1):e86917. doi: 10.1371/journal.pone.0086917. eCollection 2014.
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.
据报道，RUNX3（ runt相关转录因子3）可抑制不同人类癌症中的肿瘤发生和转移。在本研究中，我们使用组织芯片（TMA）来确定RUNX3在前列腺癌进展中的意义。我们的结果显示，与肿瘤相邻的正常前列腺组织相比，RUNX3在前列腺癌组织中异位表达，且RUNX3染色减少与TNM分期显著相关。此外，我们证明RUNX3过表达抑制前列腺癌细胞迁移和侵袭，这是由于基质金属蛋白酶组织抑制剂-2（TIMP-2）上调，随后在体外抑制金属蛋白酶-2（MMP-2）表达和活性。敲低RUNX3表达打破了TIMP-2/MMP-2的平衡，而沉默TIMP-2则导致前列腺细胞中MMP-2表达受到抑制。我们还表明，恢复RUNX3可减少血管内皮生长因子（VEGF）分泌，并抑制内皮细胞生长和管腔形成。引人注目的是，RUNX3在体内可抑制肿瘤转移和血管生成。总之，我们的结果支持RUNX3在人类前列腺癌中的肿瘤抑制作用，并为该疾病的靶向治疗发展提供了见解。
