Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis
Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis
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DOI：
10.1038/s41388-019-0735-4
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发表时间：
2019-06-06
期刊：
影响因子：
8
通讯作者：
Luo, Yunping
中科院分区：
文献类型：
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作者：
Chen, Chong;Bai, Lipeng;Luo, Yunping
代谢和酸性微环境的改变在促进肿瘤恶性特征中发挥重要作用。一小群癌症干细胞（CSC）被认为是保留肿瘤复发、耐药和转移的治疗靶点。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，我们发现在体外和体内，细胞外酸化速率、葡萄糖摄取和乳酸分泌均被 LIN28B 敲低所抑制。重要的是，代谢分析表明，CSC 具有增强的有氧糖酵解代谢特征，并且糖酵解产物乳酸进一步促进癌症相关的干性特性。 LIN28B 沉默会抑制 MYC 表达，从而进一步增加 miR-34a-5p 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水平与人乳腺癌患者的高LIN28B表达和不良预后相关。值得注意的是，在人乳腺癌细胞 MDA-MB-231 的免疫缺陷原位小鼠模型中，通过 LIN28B 特异性抑制剂阻断 LIN28B/MYC/miR-34a-5p 信号通路可显着抑制肿瘤生长和转移。总而言之，我们的研究结果提供了针对 LIN28B 抑制 CSC 糖酵解代谢和肿瘤进展的临床前研究，这可能会提高癌症患者的治疗效果。
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.