Zheng Lufeng, Li Xiaoman, Meng Xia, Chou Jinjiang, Hu Jinhang, Zhang Feng, Zhang Zhiting, Xing Yingying, Liu Yu, Xi Tao
School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Mol Cell Endocrinol. 2016 May 15;427:133-42. doi: 10.1016/j.mce.2016.03.012. Epub 2016 Mar 12.
Patients with estrogen receptor α (ERα)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3'UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3'UTR enhances the transcriptional activity of ERα through the activation of ERα phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3'UTRs increase ERα activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3'UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3'UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer.
雌激素受体α（ERα）阳性乳腺癌患者可使用他莫昔芬等抗雌激素进行内分泌治疗；然而，患者常出现耐药性，限制了乳腺癌治疗的成功率。潜在机制仍不清楚。具体而言，许多微小RNA（miRNA）与乳腺癌他莫昔芬耐药有关，但尚无研究探讨miRNA介导的竞争性内源RNA网络（ceRNET）在他莫昔芬耐药中的作用。已揭示CYP4Z1与假基因CYP4Z2P之间的ceRNET可促进乳腺癌血管生成。然而，其在他莫昔芬耐药中的功能仍不清楚。在此我们报告，与他莫昔芬耐药的MCF-7-TamR细胞相比，MCF-7细胞中CYP4Z1和CYP4Z2P表达下调。强制上调CYP4Z1或CYP4Z2P的3'UTR水平可使MCF-7细胞对他莫昔芬产生耐药性。我们发现，CYP4Z1或CYP4Z2P的3'UTR过表达通过激活ERα磷酸化增强了ERα的转录活性。此外，我们发现CYP4Z1和CYP4Z2P的3'UTR依赖细胞周期蛋白依赖性激酶3（CDK3）增加ERα活性。报告基因和蛋白质印迹分析显示，CYP4Z1和CYP4Z2P的3'UTR作为CDK3的ceRNA。更重要的是，阻断CYP4Z1和CYP4Z2P的3'UTR可逆转MCF-7-TamR细胞中的他莫昔芬耐药性。我们的数据表明，CYP4Z1与假基因CYP4Z2P之间的ceRNET作为一个亚ceRNET促进ER阳性乳腺癌中CDK3的表达，是治疗他莫昔芬耐药乳腺癌的潜在治疗靶点。
