Farina Nicholas H, Zingiryan Areg, Akech Jacqueline A, Callahan Cody J, Lu Huimin, Stein Janet L, Languino Lucia R, Stein Gary S, Lian Jane B
Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Oncotarget. 2016 Oct 25;7(43):70462-70474. doi: 10.18632/oncotarget.11992.
While decades of research have identified molecular pathways inducing and promoting stages of prostate cancer malignancy, studies addressing dynamic changes of cancer-related regulatory factors in a prostate tumor progression model are limited. Using the TRAMP mouse model of human prostate cancer, we address mechanisms of deregulation for the cancer-associated transcription factors, Runx1 and Runx2 by identifying microRNAs with reciprocal expression changes at six time points during 33 weeks of tumorigenesis. We molecularly define transition stages from PIN lesions to hyperplasia/neoplasia and progression to adenocarcinoma by temporal changes in expression of human prostate cancer markers, including the androgen receptor and tumor suppressors, Nkx3.1 and PTEN. Concomitant activation of PTEN, AR, and Runx factors occurs at early stages. At late stages, PTEN and AR are downregulated, while Runx1 and Runx2 remain elevated. Loss of Runx-targeting microRNAs, miR-23b-5p, miR-139-5p, miR-205-5p, miR-221-3p, miR-375-3p, miR-382-5p, and miR-384-5p, contribute to aberrant Runx expression in prostate tumors. Our studies reveal a Runx/miRNA interaction axis centered on PTEN-PI3K-AKT signaling. This regulatory network translates to mechanistic understanding of prostate tumorigenesis that can be developed for diagnosis and directed therapy.
尽管数十年的研究已经确定了诱导和促进前列腺癌恶性发展阶段的分子途径，但在前列腺肿瘤进展模型中研究癌症相关调控因子动态变化的研究却很有限。利用人类前列腺癌的TRAMP小鼠模型，我们通过在33周肿瘤发生过程中的六个时间点识别表达呈反向变化的微小RNA，来探讨癌症相关转录因子Runx1和Runx2失调的机制。我们通过人类前列腺癌标志物（包括雄激素受体以及肿瘤抑制因子Nkx3.1和PTEN）表达的时间变化，从分子水平上定义了从前列腺上皮内瘤变（PIN）病变到增生/瘤变以及进展为腺癌的转变阶段。PTEN、AR和Runx因子在早期阶段同时被激活。在晚期阶段，PTEN和AR下调，而Runx1和Runx2仍然升高。靶向Runx的微小RNA，如miR-23b-5p、miR-139-5p、miR-205-5p、miR-221-3p、miR-375-3p、miR-382-5p和miR-384-5p的缺失，导致前列腺肿瘤中Runx表达异常。我们的研究揭示了一个以PTEN-PI3K-AKT信号通路为中心的Runx/微小RNA相互作用轴。这个调控网络有助于从机制上理解前列腺肿瘤发生，可用于诊断和定向治疗。
