Lai Xiaofeng, Zhang Yuan, Li Mengyang, Yu Shentong, Wang Shuiliang, Zhang Shenghang, Niu Huimin, Chen Li, Lan Xiaopeng, Zhang Jian, Chen Suning
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China.
Mol Carcinog. 2025 Apr;64(4):769-783. doi: 10.1002/mc.23878. Epub 2025 Jan 24.
Tamoxifen is one of the most frequently used endocrine medications for the treatment of estrogen receptor-positive (ER + ) breast cancer (BC). Unfortunately, tamoxifen resistance (TR) brings more challenges to the clinical treatment, and the mechanisms of TR have not yet been fully clarified. HGF/c-Met is closely associated with cancer metastasis, but whether it is involved in TR remains unclear. In our study, we found that the activation of HGF/c-Met was crucial for TR maintenance. Synergistic interaction with HOTAIR and EZH2 accelerated HGF expression by repressing miR-141/200a. Additionally, HGF/c-Met activated NF-κB, forming a positive feedback loop of EZH2/HOTAIR-miR-141/200a-HGF/c-Met-NF-κB. Our findings indicated that HGF/c-Met functioned as an important biomarker for TR, and HGF/c-Met inhibition provided a novel approach to TR treatment.
他莫昔芬是治疗雌激素受体阳性（ER+）乳腺癌（BC）最常用的内分泌药物之一。不幸的是，他莫昔芬耐药（TR）给临床治疗带来了更多挑战，且TR的机制尚未完全阐明。肝细胞生长因子/间质上皮转化因子（HGF/c-Met）与癌症转移密切相关，但它是否参与TR尚不清楚。在我们的研究中，我们发现HGF/c-Met的激活对TR的维持至关重要。与HOTAIR和EZH2的协同相互作用通过抑制miR-141/200a加速了HGF的表达。此外，HGF/c-Met激活核因子κB（NF-κB），形成了EZH2/HOTAIR-miR-141/200a-HGF/c-Met-NF-κB的正反馈环。我们的研究结果表明，HGF/c-Met作为TR的重要生物标志物发挥作用，抑制HGF/c-Met为TR治疗提供了一种新方法。
