miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT.
miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT.
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作者：
Src酪氨酸激酶（Src）参与前列腺癌骨转移和去势抵抗的发生。Src抑制剂目前正在针对这类疾病的临床试验中进行测试。了解Src抑制剂的分子和细胞作用是未来改善这一系列治疗的关键。在这里，我们描述了microRNA（miRNA）的表达谱调制的Src抑制剂，并证明miR-30家族成员是最显着的诱导物种。与其肿瘤抑制作用一致，miR-30被致癌信号如表皮生长因子（EGF）和肝细胞生长因子（HGF）下调，并且通常在前列腺癌标本中表达不足。许多上皮间质转化（EMT）相关基因是miR-30的预测靶点。在这些基因中，Ets相关基因（ERG）是前列腺癌中最常见的过表达的癌基因，其通过TMPRSS 2的启动子上游序列与ERG的编码序列之间的基因组融合事件激活。我们通过ERG 3′ UTR报告基因和突变分析表明，ERG是miR-30的直接靶点。miR-30在前列腺癌细胞中的过表达抑制EMT表型并抑制细胞迁移和侵袭。它还抑制VCaP细胞的体外和体内生长，VCaP细胞的增殖依赖于TMPRSS 2-ERG。TMPRSS 2-ERG通常在转录水平受雄激素调节。我们的发现揭示了一种新的转录后机制，即Src对TMPRSS 2-ERG的调节和miR-30对生长信号的调节，为Src抑制剂靶向ERG阳性去势抵抗性肿瘤提供了理论基础。
Src tyrosine kinase (Src) is implicated in the development of bone metastasis and castration-resistance of prostate cancer. Src inhibitors are currently being tested in clinical trials for such diseases. Understanding the molecular and cellular actions of Src inhibitors holds the key to future improvement of this line of therapy. Here we describe the microRNA (miRNA) expression profiles modulated by two Src inhibitors and demonstrate that the miR-30 family members are the most prominently induced species. Consistent with its tumor suppressor role, miR-30 is downmodulated by oncogenic signals such as epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and is generally underexpressed in prostate cancer specimens. A number of epithelial to mesenchymal transition (EMT)-associated genes are predicted targets of miR-30. Among these genes the Ets Related Gene (ERG) is the most frequently overexpressed-oncogene in prostate cancer activated by genomic fusion events between promoter upstream sequences of the TMPRSS2 and coding sequences of ERG. We showed by ERG 3′UTR-reporter and mutagenesis assays that ERG is a direct target of miR-30. Overexpression of miR-30 in prostate cancer cells suppresses EMT phenotypes and inhibits cell migration and invasion. It also inhibits the in vitro and in vivo growth of VCaP cells, which depends on TMPRSS2-ERG for proliferation. TMPRSS2-ERG is generally regulated by androgen at the transcriptional level. Our finding reveals a new post-transcriptional mechanism of TMPRSS2-ERG regulation by Src and growth signals via miR-30 providing a rationale for targeting ERG positive castration resistant tumors with Src inhibitors.
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靶向前列腺癌中酪氨酸激酶和自噬。
影响因子：
3
作者：
Kung HJ
通讯作者：
Kung HJ
DOI：
10.1126/science.1178124
发表时间：
2009-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mani RS;Tomlins SA;Callahan K;Ghosh A;Nyati MK;Varambally S;Palanisamy N;Chinnaiyan AM
通讯作者：
Chinnaiyan AM
影响因子：
30.8
作者：
King, Jennifer C.;Xu, Jin;Wongvipat, John;Hieronymus, Haley;Carver, Brett S.;Leung, David H.;Taylor, Barry S.;Sander, Chris;Cardiff, Robert D.;Couto, Suzana S.;Gerald, William L.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
11.2
作者：
Gupta, Santosh;Iljin, Kristiina;Kallioniemi, Olli
通讯作者：
Kallioniemi, Olli
DOI：
10.1073/pnas.0711711105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Klezovitch, Olga;Risk, Michael;Vasioukhin, Valeri
通讯作者：
Vasioukhin, Valeri