Activin A Enhances Prostate Cancer Cell Migration Through Activation of Androgen Receptor and Is Overexpressed in Metastatic Prostate Cancer
Activin A Enhances Prostate Cancer Cell Migration Through Activation of Androgen Receptor and Is Overexpressed in Metastatic Prostate Cancer
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DOI：
10.1359/jbmr.090219
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发表时间：
2009-07-01
影响因子：
6.2
通讯作者：
Huang, Ko-En
中科院分区：
文献类型：
--
作者：
Kang, Hong-Yo;Huang, Hsuan-Ying;Huang, Ko-En
骨转移是前列腺癌死亡的主要原因。尽管已知激活素A抑制前列腺癌细胞生长并促进细胞凋亡，但在前列腺癌的骨转移阶段中升高的激活素A与升高的血清前列腺特异性抗原（PSA）水平的相关性已得到充分证实。解释激活素A这些矛盾作用的分子机制以及激活素A如何影响前列腺癌骨转移的进展仍不清楚。通过比较原发性前列腺癌活检组织的表达谱，有和没有骨转移，我们发现，激活素A的表达增加的情况下，骨转移倾向，并与雄激素受体（AR），PSA表达，和格里森评分增加。激活素A促进前列腺癌细胞向成骨细胞迁移，通过与AR启动子结合，通过Smads提高AR基因转录，并诱导AR核转位与Smad 3相互作用。通过siRNA敲低Smad 3降低激活素A促进的AR表达和癌细胞迁移。AR的过表达逆转了Smad 3-siRNA对激活素A介导的细胞向成骨细胞迁移的抑制。这些数据表明，通过Smads激活AR是激活素A促进的前列腺癌细胞迁移到骨基质所必需的，从而促进骨转移表型，并且激活素A-Smad-AR轴可以被认为是骨转移性疾病的治疗靶点。骨矿研究杂志2009;24：1180-1193。在线发表于2009年2月16日; doi：10.1359/JBMR.090219
Bone metastasis is the major cause of mortality associated with prostate cancer. Whereas activin A is known to inhibit prostate cancer cell growth and promote apoptosis, the correlation of elevated activin A with increasing serum prostate-specific antigen (PSA) levels in bone metastatic stages of prostate cancer is well documented. The molecular mechanisms explaining these paradoxical effects of activin A and how activin A influences the progression of prostate cancer with bone metastasis remain unclear. By comparing expression profiles of primary prostate cancer biopsies, with and without bone metastasis, we discovered that the expression of activin A is increased in cases with bone metastatic propensity and correlates with increased androgen receptor (AR), PSA expression, and Gleason scores. Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3. Knockdown of Smad3 by siRNA decreases activin A-promoted AR expression and cancer cell migration. Overexpression of AR reversed Smad3-siRNA suppression on activin A-mediated cell migration to osteoblasts. These data suggest that activation of the AR through Smads is required for activin A-promoted prostate cancer cell migration to bone matrix, thereby promoting the bone metastatic phenotype, and the activin A-Smad-AR axis may be considered a therapeutic target in bone metastatic diseases. J Bone Miner Res 2009;24:1180-1193. Published online on February 16, 2009; doi: 10.1359/JBMR.090219