Department of Pathophysiology, Weifang Medical University, Weifang, 261053, China.
Key Laboratory of Applied Pharmacology, Weifang Medical University, Weifang, 261053, China.
BMC Cancer. 2020 Jul 6;20(1):626. doi: 10.1186/s12885-020-07107-6.
The failure of treatment for breast cancer usually results from distant metastasis in which the epithelial-mesenchymal transition (EMT) plays a critical role. Hyperinsulinemia, the hallmark of Type 2 diabetes mellitus (T2DM), has been regarded as a key risk factor for the progression of breast cancer. Nuclear receptor subfamily 2, group F, member 2 (NR2F2) has been implicated in the development of breast cancer, however its contribution to insulin-induced EMT in breast cancer remains unclear.
Overexpression and knockdown of NR2F2 were used in two breast cancer cell lines, MCF-7 and MDA-MB-231 to investigate potential mechanisms by which NR2F2 leads to insulin-mediated EMT. To elucidate the effects of insulin and signaling events following NR2F2 overexpression and knockdown, Cells' invasion and migration capacity and changes of NR2F2, E-cadherin, N-cadherin and vimentin were investigated by real-time RT-PCR and western blot.
Insulin stimulation of these cells increased NR2F2 expression levels and promoted cell invasion and migration accompanied by alterations in EMT-related molecular markers. Overexpression of NR2F2 and NR2F2 knockdown demonstrated that NR2F2 expression was positively correlated with cell invasion, migration and the expression of N-cadherin and vimentin. In contrast, NR2F2 had an inverse correlation with E-cadherin expression. In MDA-MB-231, both insulin-induced cell invasion and migration and EMT-related marker alteration were abolished by NR2F2 knockdown.
These results suggest that NR2F2 plays a critical role in insulin-mediated breast cancer cell invasion, migration through its effect on EMT.
乳腺癌治疗失败通常是由于远处转移引起的，而上皮-间质转化（EMT）在此过程中起着关键作用。2 型糖尿病（T2DM）的标志是高胰岛素血症，已被认为是乳腺癌进展的关键危险因素。核受体亚家族 2，组 F，成员 2（NR2F2）已被认为与乳腺癌的发生有关，但其在胰岛素诱导的乳腺癌 EMT 中的作用尚不清楚。
在两种乳腺癌细胞系 MCF-7 和 MDA-MB-231 中过表达和敲低 NR2F2，以研究 NR2F2 导致胰岛素介导的 EMT 的潜在机制。为了阐明胰岛素和 NR2F2 过表达和敲低后信号事件的影响，通过实时 RT-PCR 和 Western blot 研究了细胞侵袭和迁移能力以及 NR2F2、E-钙粘蛋白、N-钙粘蛋白和波形蛋白的变化。
这些细胞中胰岛素的刺激增加了 NR2F2 的表达水平，并促进了细胞侵袭和迁移，同时 EMT 相关分子标志物也发生了变化。过表达 NR2F2 和敲低 NR2F2 表明，NR2F2 的表达与细胞侵袭、迁移以及 N-钙粘蛋白和波形蛋白的表达呈正相关。相比之下，NR2F2 与 E-钙粘蛋白的表达呈负相关。在 MDA-MB-231 中，NR2F2 敲低可消除胰岛素诱导的细胞侵袭和迁移以及 EMT 相关标志物的改变。
这些结果表明，NR2F2 通过对 EMT 的影响，在胰岛素介导的乳腺癌细胞侵袭和迁移中发挥关键作用。
