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.

中文翻译：

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靶向LIN28B可重新编程肿瘤葡萄糖代谢和酸性微环境，以抑制癌症的干性和转移。

代谢和酸性微环境的改变在促进肿瘤恶性特征中起重要作用。少数癌症干细胞（CSC）被视为保留肿瘤复发，耐药性和转移的治疗靶标。然而，调节CSCs代谢的分子机制仍然知之甚少。在这项研究中，我们证明了干性基因LIN28B在维持CSCs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在体外和体内均可抑制细胞外酸化，葡萄糖摄取和乳酸分泌。重要的是，代谢分析显示CSC具有增强的有氧糖酵解代谢特性，而糖酵解产物乳酸进一步促进了与癌症相关的干性。LIN28B沉默抑制MYC表达，从而进一步提高miR-34a-5p水平。此外，MYC siRNA或miR-34a-5p模拟物可抑制人乳腺癌细胞系MDA-MB-231的糖酵解代谢。临床上，高MYC和低miR-34a-5p水平与人乳腺癌患者中高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。综上所述，我们的研究结果提供了针对LIN28B抑制CSCs糖酵解代谢和肿瘤进展的临床前研究，这可能会改善癌症患者的治疗效果。