MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha
MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha
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DOI：
10.1007/s13277-016-5200-1
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发表时间：
2016-10-01
期刊：
影响因子：
--
通讯作者：
Han, Shumei
中科院分区：
文献类型：
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作者：
Han, Li;Liu, Bo;Han, Shumei
转移已经成为雌激素受体α（ER α）阴性乳腺癌治疗的主要挑战。在这里，我们发现miR-497和雌激素相关受体α（ERR α）之间呈负相关，ER α阴性乳腺癌中过表达的核受体。通过si-RNA靶向抑制ERR α增加miR-497表达，而ERR α的过表达抑制miR-497表达。进一步的研究表明，miR-497通过结合ERR alpha的3 'UTR区域靶向ERR alpha。荧光素酶检测和ChIP检测证实ER α直接调控miR-497的转录，提示ER α阴性乳腺癌中ER α的缺失降低了miR-497的水平。此外，miR-497的过表达不仅抑制了ERR α表达，而且降低了MIF水平和MMP 9活性，这导致ER α阴性乳腺癌的细胞增殖、迁移和侵袭显著降低。总之，我们的研究结果表明，在ER α阴性乳腺癌中，低水平的ER α降低了miR-497的表达，这促进了ERR α的表达，通过增加MIF表达和MMP 9活性来增强细胞增殖、迁移和侵袭。
Metastasis has become the main challenge for treatment of estrogen receptor alpha (ER alpha) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERR alpha), a nuclear receptor overexpressed in ER alpha negative breast cancer. Targeted inhibition of ERR alpha by si-RNA increased miR-497 expression while overexpression of ERR alpha inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERR alpha by binding to the 3'UTR region of ERR alpha. Luciferase assay and ChIP assay confirmed that ER alpha directly regulated the transcription of miR-497, suggesting that loss of ER alpha lowered miR-497 level in ER alpha negative breast cancer. Further, overexpression of miR-497 not only inhibited ERR alpha expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ER alpha negative breast cancer. Taken together, our findings suggested that, in ER alpha negative breast cancer, the low level of ER alpha reduced miR-497 expression, which promoted ERR alpha expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.