Androgen depletion up-regulates cadherin-11 expression in prostate cancer.
Androgen depletion up-regulates cadherin-11 expression in prostate cancer.
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DOI：
10.1002/path.2687
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发表时间：
2010-05
影响因子：
7.3
通讯作者：
Lin, Sue-Hwa
中科院分区：
文献类型：
--
作者：
Lee, Yu-Chen;Cheng, Chien-Jui;Huang, Miao;Bilen, Mehmet A.;Ye, Xiangcang;Navone, Nora M.;Chu, Khoi;Kao, Hsin-Hsin;Yu-Lee, Li-Yuan;Wang, Zhengxin;Lin, Sue-Hwa
患有去势抵抗性前列腺癌（PCa）的男性经常发生骨转移。这种关联的原因尚不清楚。我们先前已经表明，钙粘蛋白-11（也称为OB-钙粘蛋白），一种介导成骨细胞粘附的嗜同性细胞粘附分子，在PCa向骨的转移中起作用。在这里，我们报告，雄激素剥夺治疗上调钙粘蛋白-11在前列腺癌的表达。在人类前列腺癌标本中，免疫组化染色显示，22/26（85%）原发性前列腺癌肿瘤与去势抵抗前列腺癌表达钙粘蛋白-11。相比之下，50例雄激素依赖性PCa肿瘤中只有7例（14%）表达钙粘蛋白-11。在MDA-PCa-2b异种移植动物模型中，钙粘蛋白-11在去势后复发的肿瘤中表达。在PCa细胞系中，钙粘蛋白-11和雄激素受体（AR）的表达之间存在负相关，并且钙粘蛋白-11在AR阳性细胞系（包括LNCaP、C4- 2B 4和VCaP细胞）中以非常低的水平表达或不表达。我们发现AR可能通过间接机制调节PCa中钙粘蛋白-11的表达。尽管AR阴性PC 3细胞中AR的再表达导致钙粘蛋白-11表达的抑制，但培养基中雄激素的消耗或C4- 2B 4细胞或VCaP细胞中通过RNA干扰下调AR仅产生钙粘蛋白-11表达的适度增加。启动子分析表明，钙粘蛋白-11启动子不含典型的AR结合元件，AR对钙粘蛋白-11启动子活性有一定的抑制作用，提示AR不直接调节钙粘蛋白-11的表达。总之，这些结果表明，雄激素剥夺上调钙粘蛋白-11在前列腺癌中的表达，这可能有助于PCa转移到骨。我们的研究表明，阻断钙粘蛋白-11的表达或功能的治疗策略，可考虑应用雄激素消融治疗。
Men with castration-resistant prostate cancer (PCa) frequently develop metastasis in bone. The reason for this association is unclear. We have previously shown that cadherin-11 (also known as OB-cadherin), a homophilic cell adhesion molecule that mediates osteoblast adhesion, plays a role in the metastasis of PCa to bone. Here, we report that androgen deprivation therapy upregulates cadherin-11 expression in PCa. In human PCa specimens, immunohistochemical staining showed that 22 of 26 (85%) primary PCa tumors from men with castration-resistant PCa expressed cadherin-11. In contrast, only 7 of 50 (14%) androgen-dependent PCa tumors expressed cadherin-11. In the MDA-PCa-2b xenograft animal model, cadherin-11 was expressed in the recurrent tumors following castration. In the PCa cell lines, there is an inverse correlation between expression of cadherin-11 and androgen receptor (AR), and cadherin-11 is expressed in very low levels or not expressed in AR positive cell lines, including LNCaP, C4-2B4, and VCaP cells. We showed that AR likely regulates cadherin-11 expression in PCa through an indirect mechanism. Although re-expression of AR in the AR-negative PC3 cells led to the inhibition of cadherin-11 expression, depletion of androgen from the culture medium or down regulation of AR by RNA interference in the C4-2B4 cells or VCaP cells only produce a modest increase of cadherin-11 expression. Promoter analysis indicated that cadherin-11 promoter does not contain a typical AR binding element, and AR elicits a modest inhibition of cadherin-11 promoter activity, suggesting that AR does not regulate cadherin-11 expression directly. Together, these results suggest that androgen deprivation upregulates cadherin-11 expression in prostate cancer and this may contribute to the metastasis of PCa to bone. Our study suggests that therapeutic strategies that block cadherin-11 expression or function may be considered when applying androgen ablation therapy.
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影响因子：
10.5
作者：
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