miR-154* and miR-379 in the DLK1-DIO3 microRNA mega-cluster regulate epithelial to mesenchymal transition and bone metastasis of prostate cancer.
miR-154* and miR-379 in the DLK1-DIO3 microRNA mega-cluster regulate epithelial to mesenchymal transition and bone metastasis of prostate cancer.
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在DLK1-DIO3 MieRORNA Mega簇中的miR-154*和miR-379调节上皮对中充质转变和前列腺癌的骨转移。
DOI：
10.1158/1078-0432.ccr-14-1784
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发表时间：
2014-12-15
期刊：
影响因子：
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通讯作者：
Chung LW
中科院分区：
文献类型：
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作者：
Gururajan M;Josson S;Chu GC;Lu CL;Lu YT;Haga CL;Zhau HE;Liu C;Lichterman J;Duan P;Posadas EM;Chung LW
delta-样1同源物-去碘酶，碘甲状腺原氨酸3 （DLK1-DIO3）簇中的microrna已被证明对胚胎发育和上皮向间质转化（EMT）至关重要。转移性癌症患者血清中DLK1-DIO3簇mirna升高。然而，这些mirna在癌细胞EMT和转移中的生物学功能尚不清楚。我们之前证明了miR-409-3p/5p在前列腺癌（PCa）中的致癌和转移作用。在本研究中，我们在细胞系模型和临床标本中定义了miR-154*和miR-379这两个关键成员在PCa进展和骨转移中的作用。在小鼠模型中对miR-154*和miR-379进行遗传操作，以确定它们在肿瘤生长、EMT和骨转移中的作用。我们利用原位杂交和量子点标记技术检测了miR-154*在前列腺癌临床样本和骨转移样本中的表达。骨转移性PCa细胞系和组织中miR-154*和miR-379表达升高，miR-379表达与PCa患者无进展生存期相关。在小鼠心脏内接种miR-154*抑制剂处理的骨转移性ARCaPM PCa细胞（模拟全身传播）导致骨转移减少和生存率提高。miR-154*和miR-379通过促进肿瘤生长、EMT和骨转移在前列腺癌生物学中发挥重要作用。这一发现具有特殊的翻译意义，因为DLK1-DIO3簇中的mirna可能是治疗骨转移性PCa的有吸引力的生物标志物和可能的治疗靶点。
MicroRNAs in the delta-like 1 homolog - deiodinase, iodothyronine 3 (DLK1-DIO3) cluster have been shown to be critical for embryonic development and epithelial to mesenchymal transition (EMT). DLK1-DIO3 cluster miRNAs are elevated in the serum of metastatic cancer patients. However, the biological functions of these miRNAs in the EMT and metastasis of cancer cells are poorly understood. We previously demonstrated the oncogenic and metastatic role of miR-409-3p/5p, a member of this cluster, in prostate cancer (PCa). In this study, we defined the role of miR-154* and miR-379, two key members of this cluster, in PCa progression and bone metastasis in both cell line models and clinical specimens. Genetic manipulation of miR-154* and miR-379 was performed to determine their role in tumor growth, EMT and bone metastasis in mouse models. We determined the expression of miR-154* in prostate cancer clinical samples and bone metastasis samples using in situ hybridization and quantum dot labeling. Elevated expression of miR-154* and miR-379 was observed in bone metastatic PCa cell lines and tissues, and miR-379 expression correlated with PCa patient progression-free survival. Intracardiac inoculation (to mimic systemic dissemination) of miR-154* inhibitor-treated bone metastatic ARCaPM PCa cells in mice led to decreased bone metastasis and increased survival. miR-154* and miR-379 play important roles in PCa biology by facilitating tumor growth, EMT and bone metastasis. This finding has particular translational importance since miRNAs in the DLK1-DIO3 cluster can be attractive biomarkers and possible therapeutic targets to treat bone metastatic PCa.