Han Li, Liu Bo, Jiang Lixi, Liu Junyan, Han Shumei
Department of Internal Medicine Oncology, Shandong Tumor Hospital and Institute, No.440 Ji Yan Road, Jinan, 250117, China.
Tumour Biol. 2016 Oct;37(10):13205-13214. doi: 10.1007/s13277-016-5200-1. Epub 2016 Jul 25.
Metastasis has become the main challenge for treatment of estrogen receptor alpha (ERα) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERRα), a nuclear receptor overexpressed in ERα negative breast cancer. Targeted inhibition of ERRα by si-RNA increased miR-497 expression while overexpression of ERRα inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERRα by binding to the 3'UTR region of ERRα. Luciferase assay and ChIP assay confirmed that ERα directly regulated the transcription of miR-497, suggesting that loss of ERα lowered miR-497 level in ERα negative breast cancer. Further, overexpression of miR-497 not only inhibited ERRα expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ERα negative breast cancer. Taken together, our findings suggested that, in ERα negative breast cancer, the low level of ERα reduced miR-497 expression, which promoted ERRα expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.
转移已成为雌激素受体α（ERα）阴性乳腺癌治疗的主要挑战。在此，我们发现miR-497与雌激素相关受体α（ERRα）之间呈负相关，ERRα是一种在ERα阴性乳腺癌中过表达的核受体。通过小干扰RNA（si-RNA）靶向抑制ERRα可增加miR-497的表达，而ERRα的过表达则抑制miR-497的表达。进一步研究表明，miR-497通过与ERRα的3'非翻译区（3'UTR）结合来靶向ERRα。荧光素酶报告基因检测和染色质免疫沉淀检测证实，ERα直接调控miR-497的转录，这表明在ERα阴性乳腺癌中，ERα的缺失降低了miR-497的水平。此外，miR-497的过表达不仅抑制了ERRα的表达，还降低了巨噬细胞移动抑制因子（MIF）水平和基质金属蛋白酶9（MMP9）的活性，这导致ERα阴性乳腺癌细胞的增殖、迁移和侵袭显著减少。综上所述，我们的研究结果表明，在ERα阴性乳腺癌中，ERα水平降低会减少miR-497的表达，从而促进ERRα的表达，而ERRα通过增加MIF表达和MMP9活性来增强细胞的增殖、迁移和侵袭。
