miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect
miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect
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miR-30a-5p通过抑制LDHA介导的Warburg效应抑制乳腺肿瘤生长和转移
DOI：
10.1016/j.canlet.2017.04.034
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发表时间：
2017-08-01
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：
Li, Ling;Kang, Lei;Ye, Qinong
乳酸脱氢酶A(LDHA)是一种调节有氧糖酵解的关键酶，在许多人类癌症中过度表达，与不良的临床预后相关。有氧糖酵解是癌症的一个标志，针对其调节因子的药物，包括LDHA，正在开发中。然而，LDHA抑制的机制以及LDHA抑制剂在癌细胞中的生理意义尚不清楚。在这里，我们证明了microRNA-30a-5p(miR-30a-5p)通过直接靶向其3‘-UTR而抑制LDHA的表达。通过抑制LDHA，miR-30a-5p通过降低乳腺癌细胞的葡萄糖摄取、乳酸生成、ATP生成和胞外酸化率(ECAR)，并增加氧耗率(OCR)来抑制糖酵解。重要的是，miR-30a-5p调控的糖酵解对其在体内外调控乳腺肿瘤的生长和转移起着至关重要的作用。乳腺癌患者miR-30a-5p的表达与LDHA的表达呈负相关。此外，通过PET扫描评估肿瘤中葡萄糖摄取增加的患者显示miR-30a-5p表达减少，LDHA表达增加。我们的发现为miR-30a-5p通过抑制LDHA在乳腺癌中作为肿瘤抑制因子的作用提供了线索。通过miR-30a-5p靶向LDHA可能是一种潜在的乳腺癌治疗策略。(C)2017爱思唯尔B.V.保留所有权利。
Lactate dehydrogenase A (LDHA), a key enzyme regulating aerobic glycolysis, is overexpressed in many human cancers, and correlates with poor clinical outcomes. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including LDHA, are being developed. However, the mechanisms of LDHA inhibition and the physiological significance of the LDHA inhibitors in cancer cells are unclear. Here, we show that microRNA-30a-5p (miR-30a-5p) suppresses LDHA expression by directly targeting its 3 '-UTR. Through inhibition of LDHA, miR-30a-5p dampens glycolysis by decreasing glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in breast cancer cells. Importantly, glycolysis regulated by miR-30a-5p is critical for its regulating breast tumor growth and metastasis both in vitro and in vivo. In breast cancer patients, miR-30a-5p expression is negatively correlated with LDHA expression. Moreover, patients who had increased glucose uptake in tumors assessed by PET scans showed decreased miR-30a-5p expression and increased expression of LDHA. Our findings provide clues regarding the role of miR-30a-5p as a tumor suppressor in breast cancer through the inhibition of LDHA. Targeting LDHA through miR-30a-5p could be a potential therapeutic strategy in breast cancer. (C) 2017 Elsevier B.V. All rights reserved.