lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.
lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.
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DOI：
10.1158/1541-7786.mcr-14-0251
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Zhou Q
中科院分区：
文献类型：
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作者：
Eades G;Wolfson B;Zhang Y;Li Q;Yao Y;Zhou Q
三阴性（ER-、HER 2-、PR-）乳腺癌（TNBC）是一种侵袭性疾病，预后不良，没有可用的分子靶向治疗。micRoRNA-145（miR-145）的沉默可以是基于分子谱分析和深度测序的TNBC的定义标志物。因此，检查了TNBC中miR-145下调背后的分子机制。长非编码RNA lincRNA-RoR的过表达在TNBC中充当竞争性内源RNA海绵。有趣的是，lincRNA-RoR在TNBC和转移性疾病中显著上调，并且敲低恢复miR-145表达。先前的报告表明，miR-145在一些乳腺癌中具有生长抑制活性;然而，TNBC中的当前数据表明，miR-145不影响增殖或凋亡，而是调节肿瘤细胞侵袭。对参与肿瘤侵袭的miR-145调节途径的研究揭示了一个新的靶点，即小GTd 6 ADP-核糖基化因子6（Arf 6）。随后的分析表明，ARF 6，一种已知的乳腺肿瘤细胞侵袭调节因子，在TNBC和乳腺肿瘤转移中显著上调。从机制上讲，ARF 6调节E-钙粘蛋白定位并影响细胞-细胞粘附。这些结果揭示了调节TNBC中侵袭的lincRNA-RoR/miR-145/ARF 6途径。lincRNA-RoR/miR-145/ARF 6通路对TNBC转移至关重要，可以作为改善生存的生物标志物或治疗靶点。
Triple-negative (ER-, HER2-, PR-) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of micRoRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 down-regulation in TNBC was examined. Overexpression of the long non-coding RNA, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth suppressive activity in some breast cancers; however, the current data in TNBC indicates that miR-145 does not impact proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145 regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and impacts cell-cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs. The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival.