Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
Oncogene. 2019 Jun;38(23):4527-4539. doi: 10.1038/s41388-019-0735-4. Epub 2019 Feb 11.
The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo. Importantly, metabolic analyses reveal that CSCs have enhanced aerobic glycolysis metabolic characteristics and the glycolytic product lactate further promotes cancer associated stemness properties. LIN28B silencing suppresses MYC expression that further increases miR-34a-5p level. Furthermore, the glycolysis metabolism of human breast cancer cell line MDA-MB-231 is suppressed by either MYC siRNA or miR-34a-5p mimic. Clinically, high MYC and low miR-34a-5p level are correlated with high LIN28B expression and poor prognosis in human breast cancer patients. Notably, blocking LIN28B/MYC/miR-34a-5p signaling pathway by LIN28B-specific inhibitor causes dramatic inhibition of tumor growth and metastasis in immunodeficient orthotopic mouse models of human breast cancer cell MDA-MB-231. Taken together, our findings offer a preclinical investigation of targeting LIN28B to suppress CSCs glycolysis metabolism and tumor progression that may improve the therapeutic benefit for cancer patients.
代谢改变和酸性微环境在促进肿瘤恶性特征方面发挥着重要作用。一小部分癌症干细胞（CSC）被认为是治疗靶点，以保留肿瘤复发、耐药和转移。然而，调节 CSC 代谢的分子机制仍知之甚少。在这项研究中，我们证明了干性基因 LIN28B 在维持 CSC 糖酵解代谢中的基本作用。使用表达 LIN28B 的癌细胞系，我们发现 LIN28B 敲低在体外和体内均抑制细胞外酸化、葡萄糖摄取和乳酸分泌的速率。重要的是，代谢分析表明 CSCs 具有增强的有氧糖酵解代谢特征，而糖酵解产物乳酸进一步促进了癌症相关的干性特性。LIN28B 沉默抑制 MYC 的表达，进一步增加 miR-34a-5p 的水平。此外，人乳腺癌细胞系 MDA-MB-231 的糖酵解代谢被 MYC siRNA 或 miR-34a-5p 模拟物抑制。临床上，高 MYC 和低 miR-34a-5p 水平与人类乳腺癌患者中高 LIN28B 表达和预后不良相关。值得注意的是，LIN28B 特异性抑制剂阻断 LIN28B/MYC/miR-34a-5p 信号通路导致人乳腺癌细胞 MDA-MB-231 的免疫缺陷原位小鼠模型中的肿瘤生长和转移明显抑制。总之，我们的研究结果为靶向 LIN28B 抑制 CSC 糖酵解代谢和肿瘤进展提供了临床前研究，可能提高癌症患者的治疗效益。
