TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis.
TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis.
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TOP1MT 缺陷通过增强 LDHA 表达和有氧糖酵解促进 GC 侵袭和迁移
DOI：
10.1530/erc-17-0058
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发表时间：
2017-11
影响因子：
3.9
通讯作者：
Liao W
中科院分区：
文献类型：
--
作者：
Wang H;Zhou R;Sun L;Xia J;Yang X;Pan C;Huang N;Shi M;Bin J;Liao Y;Liao W
有氧糖酵解在癌症进展中起着重要作用。必须探索调节癌症有氧糖酵解的新靶基因以改善患者预后。线粒体拓扑异构酶 I (TOP1MT) 缺陷会抑制正常细胞中的葡萄糖氧化代谢，但会增强糖酵解。在这里，我们研究了 TOP1MT 在胃癌 (GC) 中的作用，并试图确定其潜在机制。通过体外和体内实验并分析GC患者的临床病理特征，我们发现GC样本中的TOP1MT表达低于邻近的非恶性组织。 TOP1MT 敲低显着促进体外和体内 GC 迁移和侵袭。重要的是，TOP1MT 沉默增加了 GC 中的葡萄糖消耗、乳酸产生、葡萄糖转运蛋白 1 表达和上皮间质转化 (EMT)。此外，TOP1MT 诱导的葡萄糖代谢调节与乳酸脱氢酶 A (LDHA) 表达显着相关。对295例GC患者临床数据的回顾性分析表明，TOP1MT低表达与淋巴结转移、复发和高死亡率相关。 TOP1MT 缺陷通过刺激 LDHA 增强葡萄糖有氧糖酵解，从而促进 GC 进展。
Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.