Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.
Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.
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雌激素调节 miRNA 表达：雌激素受体和 miR-124/AKT2 在肿瘤生长和血管生成中的意义
DOI：
10.18632/oncotarget.9230
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Jiang BH
中科院分区：
文献类型：
--
作者：
Jiang CF;Li DM;Shi ZM;Wang L;Liu MM;Ge X;Liu X;Qian YC;Wen YY;Zhen LL;Lin J;Liu LZ;Jiang BH
目前已知雌激素在乳腺癌的发生发展中起着重要作用，但其潜在的分子机制仍有待阐明。越来越多的证据表明，microRNAs在包括BC在内的各种人类癌症中发挥着重要作用。在本研究中，我们发现在受雌激素调控的microRNA中，miR-124是最显著下调的miRNA。雌激素(E2)可下调雌激素受体(ER)阳性BC细胞中miR-124的表达，miR-124过表达抑制BC细胞的增殖、迁移和侵袭，而抗miR-124抑制剂抑制miR-124具有相反的细胞功能。在E2作用下，miR-124对MCF7细胞功能的抑制作用强于对MDA-MB-231细胞的抑制作用。此外，我们发现雌激素诱导的miR-124下调需要ERα，而不是ERβ。此外，已知的癌基因AKT2是miR-124的一个新的直接靶点。乳腺癌组织中Akt2表达水平与miR-124表达水平呈负相关。Akt2在癌组织中高表达，ERα阳性癌组织中Akt2的表达水平明显高于ERα阴性癌组织。与抑制miR124一致，E2处理通过ERα增加了MCF7细胞AKT2的表达水平。最后，通过靶向AKT2，miR-124在MCF7细胞中的过表达显著抑制了肿瘤生长和血管生成。我们的结果提供了一个新的ERα/miR-124/AKT2信号通路在BC发生中的功能作用的机制洞察。MIR-124和AKT2可作为ER-α阳性BC的生物标志物和未来的治疗效果。
It is currently known that estrogen plays an important role in breast cancer (BC) development, but the underlying molecular mechanism remains to be elucidated. Accumulating evidence has revealed important roles of microRNAs in various kinds of human cancers, including BC. In this study, we found that among the microRNAs regulated by estrogen, miR-124 was the most prominent downregulated miRNA. miR-124 was downregulated by estradiol (E2) treatment in estrogen receptor (ER) positive BC cells, miR-124 overexpression suppressed cell proliferation, migration and invasion in BC cells; while the suppression of miR-124 using Anti-miR-124 inhibitor had opposite cellular functions. Under the E2 treatment, miR-124 had stronger effect to inhibit cellular functions in MCF7 cells than that in MDA-MB-231 cells. In addition, we identified that ERα, but not ERβ, was required for E2-induced miR-124 downregulation. Furthermore, AKT2, a known oncogene, was a novel direct target of miR-124. AKT2 expression levels were inversely correlated with miR-124 expression levels in human breast cancer specimens. AKT2 was overexpressed in BC specimens, and its expression levels were much higher in ERα positive cancer tissues than those ERα negative cancer tissues. Consistent with miR-124 suppression, E2 treatment increased AKT2 expression levels in MCF7 cells via ERα. Finally, overexpression of miR-124 in MCF7 cells significantly suppressed tumor growth and angiogenesis by targeting AKT2. Our results provide a mechanistic insight into a functional role of new ERα/miR-124/AKT2 signaling pathway in BC development. miR-124 and AKT2 may be used as biomarkers for ERα positive BC and therapeutic effect in the future.
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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
11.5
作者：
Herynk, Matthew H.;Parra, Irma;Fuqua, Suzanne A. W.
通讯作者：
Fuqua, Suzanne A. W.
影响因子：
64.5
作者：
Hah N;Danko CG;Core L;Waterfall JJ;Siepel A;Lis JT;Kraus WL
通讯作者：
Kraus WL
DOI：
10.1073/pnas.0906947106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Castellano, Leandro;Giamas, Georgios;Stebbing, Justin
通讯作者：
Stebbing, Justin
影响因子：
--
作者：
Li, Wentao;Zang, Wenqiao;Zhai, Baoping
通讯作者：
Zhai, Baoping