A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice.
A microRNA/Runx1/Runx2 network regulates prostate tumor progression from onset to adenocarcinoma in TRAMP mice.
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DOI：
10.18632/oncotarget.11992
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Lian JB
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作者：
Farina NH;Zingiryan A;Akech JA;Callahan CJ;Lu H;Stein JL;Languino LR;Stein GS;Lian JB
虽然几十年的研究已经确定了诱导和促进前列腺癌恶变阶段的分子途径，但在前列腺癌进展模型中解决癌症相关调控因子动态变化的研究有限。使用人类前列腺癌的TRAMP小鼠模型，我们通过识别在33周的肿瘤形成过程中六个时间点具有互换表达变化的microRNAs来研究癌症相关转录因子RUNX1和Runx2的解除调控的机制。我们通过前列腺癌标志物表达的时间变化来从分子上定义从PIN病变到增生/肿瘤和进展到腺癌的过渡阶段，包括雄激素受体和肿瘤抑制因子Nkx3.1和PTEN。伴随的PTEN、AR和RUNX因子的激活发生在早期阶段。在晚期，PTEN和AR表达下调，而RUNX1和Runx2表达持续升高。靶向RUNX的microRNAs miR-23b-5p、miR-139-5p、miR-205-5p、miR-221-3p、miR-375-3p、miR-382-5p和miR-384-5p的缺失导致了RUNX在前列腺癌中的异常表达。我们的研究揭示了一个以PTEN-PI3K-AKT信号为中心的RUNX/miRNA相互作用轴。这一调节网络转化为对前列腺癌发生的机械性理解，可用于诊断和定向治疗。
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.