Li Ling, Zhang Xiujuan, Lin Yanni, Ren Xinxin, Xie Tian, Lin Jing, Wu Shumeng, Ye Qinong
Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, 100850, China.
School of Basic Medicine, Shanxi Medical University, Taiyuan, 030000, China.
Cell Death Discov. 2023 Apr 5;9(1):114. doi: 10.1038/s41420-023-01412-2.
Hexokinase 2 (HK2), a critical rate-limiting enzyme in the glycolytic pathway catalyzing hexose phosphorylation, is overexpressed in multiple human cancers and associated with poor clinicopathological features. Drugs targeting aerobic glycolysis regulators, including HK2, are in development. However, the physiological significance of HK2 inhibitors and mechanisms of HK2 inhibition in cancer cells remain largely unclear. Herein, we show that microRNA-let-7b-5p (let-7b-5p) represses HK2 expression by targeting its 3'-untranslated region. By suppressing HK2-mediated aerobic glycolysis, let-7b-5p restrains breast tumor growth and metastasis both in vitro and in vivo. In patients with breast cancer, let-7b-5p expression is significantly downregulated and is negatively correlated with HK2 expression. Our findings indicate that the let-7b-5p/HK2 axis plays a key role in aerobic glycolysis as well as breast tumor proliferation and metastasis, and targeting this axis is a potential therapeutic strategy for breast cancer.
己糖激酶2（HK2）是糖酵解途径中催化己糖磷酸化的关键限速酶，在多种人类癌症中过度表达，并与不良的临床病理特征相关。包括HK2在内的靶向有氧糖酵解调节剂的药物正在研发中。然而，HK2抑制剂的生理意义以及HK2在癌细胞中的抑制机制在很大程度上仍不清楚。在此，我们表明微小RNA-let-7b-5p（let-7b-5p）通过靶向HK2的3'-非翻译区来抑制其表达。通过抑制HK2介导的有氧糖酵解，let-7b-5p在体外和体内均抑制乳腺肿瘤的生长和转移。在乳腺癌患者中，let-7b-5p表达明显下调，且与HK2表达呈负相关。我们的研究结果表明，let-7b-5p/HK2轴在有氧糖酵解以及乳腺肿瘤增殖和转移中起关键作用，靶向该轴是乳腺癌的一种潜在治疗策略。
