Let-7a-5p inhibits triple-negative breast tumor growth and metastasis through GLUT12-mediated warburg effect
Let-7a-5p inhibits triple-negative breast tumor growth and metastasis through GLUT12-mediated warburg effect
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Let-7a-5p通过GLUT12介导的warburg效应抑制三阴性乳腺肿瘤生长和转移
DOI：
10.1016/j.canlet.2020.09.012
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发表时间：
2020-12-28
期刊：
影响因子：
9.7
通讯作者：
Ye, Qinong
中科院分区：
文献类型：
--
作者：
Shi, Yajiao;Zhang, Yanan;Ye, Qinong
三阴性乳腺癌（TNBC）以其侵袭性表型而闻名，治疗方式有限且预后不良。瓦尔堡效应（有氧糖酵解）是癌症的标志，其作为诊断和治疗的有希望的靶点。然而，有氧糖酵解如何调节TNBC在很大程度上仍然未知。在这里，我们表明葡萄糖转运蛋白（GLUT）家族成员GLUT 12通过调节有氧糖酵解促进体外和体内TNBC肿瘤生长和转移。MicroRNA let-7a-5 p是一种肿瘤抑制因子，通过靶向其3 '-非翻译区抑制GLUT 12表达，并抑制GLUT 12介导的TNBC肿瘤生长、转移和糖酵解功能，包括葡萄糖摄取、乳酸产生、ATP产生、细胞外酸化速率和耗氧速率的改变。抑制有氧糖酵解消除了let-7a-5 p和GLUT 12调节TNBC细胞增殖、迁移和侵袭的能力。在TNBC患者中，GLUT 12显著上调，let-7a-5 p表达与GLUT 12表达呈负相关。let-7a-5 p和GLUT 12的高表达分别预测更好和更差的临床结局。总之，我们的结果表明let-7a-5 p/GLUT 12轴在TNBC肿瘤生长和转移以及有氧糖酵解中起关键作用，并且是TNBC治疗的潜在靶标。
Triple-negative breast cancer (TNBC) is known for its aggressive phenotype with limited treatment modalities and poor prognosis. The Warburg effect (aerobic glycolysis) is a hallmark of cancer that serves as a promising target for diagnosis and therapy. However, how aerobic glycolysis regulates TNBC remains largely unknown. Here, we show that the glucose transporter (GLUT) family member GLUT12 promotes TNBC tumor growth and metastasis in vitro and in vivo through regulating aerobic glycolysis. MicroRNA let-7a-5p, a tumor suppressor, inhibited GLUT12 expression by targeting its 3'-untranslated region, and suppressed GLUT12-mediated TNBC tumor growth, metastasis, and glycolytic function, including alterations of glucose uptake, lactate production, ATP generation, extracellular acidification rate, and oxygen consumption rate. Inhibiting aerobic glycolysis abolished the ability of let-7a-5p and GLUT12 to regulate TNBC cell proliferation, migration and invasion. In TNBC patients, GLUT12 was significantly upregulated, and let-7a-5p expression was inversely correlated with GLUT12 expression. High expression of let-7a-5p and GLUT12 predicted better and worse clinical outcomes, respectively. Taken together, our results indicate that the let-7a-5p/GLUT12 axis plays key roles in TNBC tumor growth and metastasis, and aerobic glycolysis, and is a potential target for TNBC treatment.