Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Prostate. 2012 Nov;72(15):1659-68. doi: 10.1002/pros.22519. Epub 2012 Apr 2.
The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer.
Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors.
The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice.
These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.
黏蛋白 1（MUC1）异二聚体癌蛋白在具有侵袭性病理和临床特征的人类前列腺癌中过度表达。然而，关于 MUC1 在前列腺癌中的功能作用，人们知之甚少。
通过 RT-PCR、免疫印迹和 AR 启动子激活来确定 MUC1-C 对雄激素受体（AR）表达的影响。进行共免疫沉淀、直接结合测定和染色质免疫沉淀（ChIP）研究，以评估 MUC1-C 和 AR 之间的相互作用。分析细胞的侵袭、在去雄激素培养基中的生长以及对 MUC1-C 抑制剂的敏感性。
本研究在雄激素依赖性 LNCaP 和 LAPC4 前列腺癌细胞中表明，致癌的 MUC1-C 亚基抑制 AR 表达。结果表明，MUC1-C 通过涉及 miR-135b 介导的 AR mRNA 水平下调的转录后机制激活。结果进一步表明，MUC1-C 通过 MUC1-C 细胞质结构域与 AR DNA 结合结构域（DBD）之间的直接相互作用与 AR 形成复合物。此外，MUC1-C 与 AR 形成复合物，该复合物占据 PSA 启动子。MUC1-C 与 AR 的相互作用与上皮-间质转化（EMT）的诱导和侵袭增加有关。MUC1-C 还赋予去雄激素培养基中的生长能力，并对比卡鲁胺治疗产生抗性。此外，MUC1-C 的表达导致对 MUC1-C 抑制剂 GO-203 的敏感性，抑制体外生长。GO-203 治疗还抑制了裸鼠中已建立的肿瘤异种移植物的生长。
这些发现表明，MUC1-C 在前列腺癌细胞中抑制 AR 表达，并赋予更具侵袭性的雄激素非依赖性表型，对 MUC1-C 抑制敏感。
