Yang Mengying, Zhan Yajing, Hou Zhijie, Wang Chunli, Fan Wenjun, Guo Tao, Li Zhuoshi, Fang Lei, Lv Shasha, Li Sisi, Gu Chundong, Ye Mingliang, Qin Hongqiang, Liu Quentin, Cui Xiaonan
The First Affiliated Hospital, Dalian Medical University, Dalian, China.
Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
Front Oncol. 2022 Dec 7;12:887035. doi: 10.3389/fonc.2022.887035. eCollection 2022.
Breast cancer stem cells are responsible for cancer initiation, progression, and drug resistance. However, effective targeting strategies against the cell subpopulation are still limited. Here, we unveil two splice variants of very-low-density lipoprotein receptor, VLDLR-I and -II, which are highly expressed in breast cancer stem cells. In breast cancer cells, VLDLR silencing suppresses sphere formation abilities and tumor growth . We find that VLDLR knockdown induces transition from self-renewal to quiescence. Surprisingly, ligand-binding activity is not involved in the cancer-promoting functions of VLDLR-I and -II. Proteomic analysis reveals that citrate cycle and ribosome biogenesis-related proteins are upregulated in VLDLR-I and -II overexpressed cells, suggesting that VLDLR dysregulation is associated with metabolic and anabolic regulation. Moreover, high expression of VLDLR in breast cancer tissues correlates with poor prognosis of patients. Collectively, these findings indicate that VLDLR may be an important therapeutic target for breast cancer treatment.
乳腺癌干细胞负责癌症的起始、进展和耐药性。然而，针对该细胞亚群的有效靶向策略仍然有限。在此，我们揭示了极低密度脂蛋白受体（VLDLR）的两种剪接变体，即VLDLR-I和-II，它们在乳腺癌干细胞中高度表达。在乳腺癌细胞中，VLDLR沉默可抑制球体形成能力和肿瘤生长。我们发现，VLDLR敲低诱导细胞从自我更新转变为静止状态。令人惊讶的是，配体结合活性并不参与VLDLR-I和-II的促癌功能。蛋白质组学分析显示，在VLDLR-I和-II过表达的细胞中，柠檬酸循环和核糖体生物合成相关蛋白上调，这表明VLDLR失调与代谢和合成代谢调节有关。此外，乳腺癌组织中VLDLR的高表达与患者的不良预后相关。总之，这些发现表明VLDLR可能是乳腺癌治疗的一个重要治疗靶点。
