TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis

Abstract

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 (<i>TOP1MT</i>) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of <i>TOP1MT</i> in gastric cancer (GC) and attempted to determine the underlying mechanism. Using <i>in vitro</i> and <i>in vivo</i> experiments and analyzing the clinicopathological characteristics of patients with GC, we found that <i>TOP1MT</i> expression was lower in GC samples than in adjacent nonmalignant tissues. <i>TOP1MT</i> knockdown significantly promoted GC migration and invasion <i>in vitro</i> and <i>in vivo</i> Importantly, <i>TOP1MT</i> 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 <i>TOP1MT</i> was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low <i>TOP1MT</i> expression was associated with lymph node metastasis, recurrence and high mortality rates. <i>TOP1MT</i> deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.