Down-regulation of MicroRNAs (MiRs) 203, 887, 3619 and 182 Prevents Vimentin-triggered, Phospholipase D (PLD)-mediated Cancer Cell Invasion
Down-regulation of MicroRNAs (MiRs) 203, 887, 3619 and 182 Prevents Vimentin-triggered, Phospholipase D (PLD)-mediated Cancer Cell Invasion
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DOI：
10.1074/jbc.m115.686006
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发表时间：
2016-01-08
影响因子：
4.8
通讯作者：
Gomez-Cambronero, Julian
中科院分区：
文献类型：
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作者：
Fite, Kristen;Gomez-Cambronero, Julian
乳腺癌是女性发病率和死亡率的主要原因。转移始于上皮间充质转化(EMT)后。我们发现EMT标记与信号转导酶磷脂酶D(PLD)介导的四个microRNAs(MiRs)的表达之间存在联系。低侵袭性的MCF-7乳腺癌细胞具有低的内源性PLD酶活性和细胞侵袭力，并伴随着miR-203、-887和-3619(减少PLD2翻译和荧光素酶报告基因)和miR-182(靶向PLD1)的高表达，因此，它们是“肿瘤抑制因子样”的miR。MiR-887+miR-3619的组合使PLD酶活性丧失90%。相反，EMT后的MDA-MB-231细胞具有低miR表达、高水平PLD1/2和高侵袭性。后者通过异位导入miRs而逆转，后者通过用特定的siRNAs沉默miRs而被取消。我们确定其分子机制是E-cadherin触发EMT前细胞miRs的表达，而vientin抑制EMT后侵袭细胞miRs的表达。这项新颖的工作首次发现了一组由主要的EMT前标记激活，并被EMT后标记失活的miR，在关键的磷脂代谢酶PLD的介导下，促进了从低侵袭到高侵袭的转变。
Breast cancer is a leading cause of morbidity and mortality among women. Metastasis is initiated after epithelial-mesenchymal-transition (EMT). We have found a connection between EMT markers and the expression of four microRNAs (miRs) mediated by the signaling enzyme phospholipase D (PLD). Low aggressive MCF-7 breast cancer cells have low endogenous PLD enzymatic activity and cell invasion, concomitant with high expression of miR-203, -887, and -3619 (that decrease PLD2 translation and a luciferase reporter) and miR-182 (targeting PLD1) that are, therefore, "tumor-suppressor-like" miRs. The combination miR-887 + miR-3619 abolished >90% of PLD enzymatic activity. Conversely, post-EMT MDA-MB-231 cells have low miR expression, high levels of PLD1/2, and high aggressiveness. The latter was reversed by ectopically transfecting the miRs, which was negated by silencing miRs with specific siRNAs. We determined that the molecular mechanism is that E-cadherin triggers expression of the miRs in pre-EMT cells, whereas vimentin dampens expression of the miRs in post-EMT invasive cells. This novel work identifies for the first time a set of miRs that are activated by a major pre-EMT marker and deactivated by a post-EMT marker, boosting the transition from low invasion to high invasion, as mediated by the key phospholipid metabolism enzyme PLD.