Preclinical Research and Development, GTx, Inc, Memphis, Tennessee, United States of America.
PLoS One. 2010 Oct 27;5(10):e13637. doi: 10.1371/journal.pone.0013637.
Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3' UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues.
雄激素受体 (AR) 的功能对于男性生殖器官、肌肉、骨骼和其他组织的发育至关重要。AR 功能受损会导致雄激素不敏感综合征 (AIS)。研究了 AR 与 microRNA (miR) 信号通路之间的相互作用，以了解 miRs 在 AR 功能中的作用。通过去势抑制 Sprague-Dawley 大鼠的雄激素水平，可抑制前列腺和肌肉中大量 miR 的表达，而用 3 毫克/天二氢睾酮 (DHT) 或选择性雄激素受体调节剂治疗去势大鼠可逆转这种抑制。在 LNCaP 前列腺癌细胞或小鼠组织中特异性敲除 miR 加工酶 DICER 可抑制 AR 功能，导致 AIS。由于 miRs 的唯一功能是结合 3'UTR 并抑制靶基因的翻译，雄激素可能诱导 miRs 抑制 AR 功能的抑制剂。一致地，在 LNCaP 细胞和小鼠组织中敲低 DICER 可诱导核心抑制剂 NCoR 和 SMRT 的表达。这些研究表明 miR、核心抑制剂和 AR 之间存在反馈回路，miRs 在非癌雄激素反应性组织中 AR 功能中起着至关重要的作用。
