Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.
Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.
复制标题
DOI：
10.1158/0008-5472.can-13-0594
复制
发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Jove R
中科院分区：
文献类型：
--
作者：
Schroeder A;Herrmann A;Cherryholmes G;Kowolik C;Buettner R;Pal S;Yu H;Müller-Newen G;Jove R
雄激素受体(AR)信号在前列腺癌的进展中起重要作用。然而，雄激素剥夺和/或基于AR靶向的治疗往往会导致抵抗。在这里，我们证明了AR表达的缺失会导致前列腺癌细胞中STAT3的激活。AR下调进一步导致前列腺癌干细胞(CSC)的发展，这需要STAT3。在人类前列腺癌组织中，肿瘤干细胞标志物的升高与那些表现出高STAT3活性和低AR表达的细胞相一致。AR下调诱导的STAT3激活是通过增加IL-6的表达来实现的。用可溶性IL-6受体融合蛋白或沉默肿瘤细胞中的STAT3治疗小鼠，可显著减少前列腺癌的生长和CSCs。综上所述，这些发现表明AR和STAT3在前列腺癌的发生发展中起着相反的作用。
Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased IL-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.