Breast Disease Center, Southwest Hospital, Third Military Medical University, Gaotanyan Street 30, Chongqing 400038, PR China.
Biochem Biophys Res Commun. 2011 May 13;408(3):411-6. doi: 10.1016/j.bbrc.2011.04.035. Epub 2011 Apr 13.
Receptor activator of NF-κB (RANK) and RANK ligand (RANKL) are known to play an important role in the development and progression of breast cancer. However, the mechanisms by which stimuli regulate the expression of RANK and RANKL in breast cancer cells are largely unknown. In this study, we show that hypoxia, a common feature of malignant tumors, can enhance the expression of RANK and RANKL mRNA and protein in MDA-MB-231 and MCF-7 breast cancer cells. In addition, we found that hypoxia induced hypoxia-inducible factor-1 alpha (HIF-1α) and phosphorylation of Akt, resulting in upregulation of RANK and RANKL expression; HIF-1α-targeted siRNA and PI3K-Akt inhibitor abrogated this upregulation in MDA-MB-231 cells. Furthermore, we also observed that hypoxia accelerated RANKL-mediated cell migration, which was inhibited following HIF-1α knockdown and PI3K-Akt inhibition. Thus, we provide evidence that hypoxia upregulates RANK and RANKL expression and increases RANKL-induced cell migration via the PI3K/Akt-HIF-1α pathway.
核因子-κB（NF-κB）受体激活剂（RANK）和 RANK 配体（RANKL）在乳腺癌的发生和发展中起着重要作用。然而，刺激调节乳腺癌细胞中 RANK 和 RANKL 表达的机制在很大程度上尚不清楚。在这项研究中，我们发现，缺氧是恶性肿瘤的一个常见特征，它可以增强 MDA-MB-231 和 MCF-7 乳腺癌细胞中 RANK 和 RANKL mRNA 和蛋白的表达。此外，我们发现缺氧诱导缺氧诱导因子-1α（HIF-1α）和 Akt 的磷酸化，导致 RANK 和 RANKL 表达上调；针对 HIF-1α 的 siRNA 和 PI3K-Akt 抑制剂阻断了 MDA-MB-231 细胞中的这种上调。此外，我们还观察到缺氧加速了 RANKL 介导的细胞迁移，而 HIF-1α 敲低和 PI3K-Akt 抑制则抑制了这种迁移。因此，我们提供的证据表明，缺氧通过 PI3K/Akt-HIF-1α 途径上调 RANK 和 RANKL 的表达，并增加 RANKL 诱导的细胞迁移。
