Leung Man-Hong, Tsoi Ho, Gong Chun, Man Ellen Ps, Zona Stefania, Yao Shang, Lam Eric W-F, Khoo Ui-Soon
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
Cancers (Basel). 2020 Feb 26;12(3):533. doi: 10.3390/cancers12030533.
Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.
乳腺癌是女性最常见的癌症类型。活性氧（ROS）在调节控制细胞存活和细胞增殖的信号通路中至关重要。阿霉素等化疗药物通过诱导ROS来诱导细胞死亡。化疗耐药性的发展与对氧化应激的适应性反应有关。NRF2是对氧化应激的细胞保护反应的主要调节因子。NRF2可以通过为恶性细胞提供生长优势来增强细胞生长、抗氧化剂表达和化疗耐药性。此前，我们鉴定出核共抑制因子NCOR2的一种新型剪接变体BQ323636.1（BQ），它能够强有力地预测原发性乳腺癌中的他莫昔芬耐药性。在本研究中，我们发现BQ在表柔比星耐药细胞中过表达，并证明BQ过表达可降低表柔比星诱导的ROS水平并赋予表柔比星耐药性。使用原发性乳腺癌组织芯片进行的体内分析表明BQ表达与化疗耐药性之间存在直接关联。体外实验表明BQ可以调节NRF2转录活性并上调抗氧化剂。荧光素酶报告基因检测表明，虽然NCOR2抑制NRF2的转录活性，但BQ的存在会降低这种抑制活性。免疫共沉淀证实NCOR2可以与NRF2结合，并且这种相互作用会因BQ过表达而受到损害，从而导致NRF2的转录活性增加。我们的研究结果表明BQ可以通过干扰NCOR2的抑制活性来调节NRF2信号通路，并揭示了BQ作为乳腺癌化疗耐药性调节因子的新作用。
