Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions.
Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions.
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DOI：
10.1038/onc.2009.389
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发表时间：
2010-02-11
期刊：
影响因子：
8
通讯作者：
Lian, J. B.
中科院分区：
文献类型：
--
作者：
Akech, J.;Wixted, J. J.;Bedard, K.;van der Deen, M.;Hussain, S.;Guise, T. A.;van Wijnen, A. J.;Stein, J. L.;Languino, L. R.;Altieri, D. C.;Pratap, J.;Keller, E.;Stein, G. S.;Lian, J. B.
Runx 2是一种骨特异性转录调节因子，在高转移性前列腺癌细胞中异常表达。在这里，我们确定了Runx 2在促进肿瘤生长和骨质溶解中的功能活性。我们的研究表明，在正常前列腺上皮细胞和非转移性LNCaP前列腺癌细胞中发现了可忽略的Runx 2。在胫骨内转移模型中，高Runx 2水平与大肿瘤的发展、转移相关基因（MMP 9、MMP 13、VEGF、骨桥蛋白）的表达增加以及促进溶骨性疾病的分泌性骨吸收因子（PTHrP、IL-8）相关。Runx 2 siRNA处理PC 3细胞在体外降低了细胞通过Matrigel的迁移和侵袭，并且在体内PC 3细胞中的shRunx 2表达阻断了它们在骨微环境中存活的能力。在共培养研究中鉴定了Runx 2功能的机制，表明PC 3细胞促进破骨细胞生成并抑制成骨细胞活性。这些发现的临床意义得到了癌症进展阶段前列腺肿瘤的人类组织微阵列研究的支持，其中Runx 2在腺癌和转移性肿瘤中表达。总之，这些发现表明Runx 2是与前列腺癌转移性骨疾病相关的事件的关键调节因子。
Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies demonstrate that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin), and secreted bone resorbing factors (PTHrP, IL-8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies demonstrating that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, where Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.
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DOI：
10.1073/pnas.0409121102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Javed, A;Barnes, GL;Stein, GS
通讯作者：
Stein, GS
影响因子：
2.1
作者：
Brown, JM;Corey, E;Vessella, RL
通讯作者：
Vessella, RL
影响因子：
11.5
作者：
Guise, Theresa A.;Mohammad, Khalid S.;Chirgwin, John M.
通讯作者：
Chirgwin, John M.
影响因子：
2.8
作者：
Armstrong, Allison P.;Miller, Robert E.;Dougall, William C.
通讯作者：
Dougall, William C.
影响因子：
11.2
作者：
Barnes, GL;Hebert, KE;Gerstenfeld, LC
通讯作者：
Gerstenfeld, LC