Department of Gastroenterology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China.
Clin Transl Med. 2021 Jan;11(1):e279. doi: 10.1002/ctm2.279.
We previously identified forkhead box (FOX) O4 mRNA as a predictor in gastric cancer (GC). However, the underlying mechanism has yet to be elucidated. We aimed to illustrate the mechanism by which FOXO4 regulated glycolysis under hypoxia in GC.
FOXO4 protein expression was investigated by immunohistochemical staining of 252 GC and their normal adjacent tissues. We restored or silenced FOXO4 expression in GC cell lines to explore the underlying mechanisms.
FOXO4 was downregulated in GC. Loss of FOXO4 expression was validated in univariate and multivariate survival analysis as an independent prognostic predictor for overall survival (P < 0.05) and disease-free survival (P<0.05). Restored FOXO4 expression significantly impaired the glycolysis rate in GC cells, while silencing FOXO4 expression enhanced glycolysis rate. FOXO4 expression was inversely associated with maximum standardized uptake value in mice models and patient samples. Mechanistically, FOXO4 bound to the glycolytic enzyme lactate dehydrogenase (LDH)A promoter and inactivated its activity in a dose-dependent manner (P < 0.05). Finally, we determined that FOXO4 was a transcriptional target of hypoxia-inducible factor (HIF) -1α, which is central in response to hypoxia.
Our data suggested that FOXO4 plays a key role in the regulation of glycolysis in GC, and disrupting the HIF-1α-FOXO4-LDHA axis might be a promising therapeutic strategy for GC.
我们之前发现叉头框 O4（FOXO4）mRNA 是胃癌（GC）的预测因子。然而，其潜在机制尚未阐明。本研究旨在阐明 FOXO4 在 GC 缺氧条件下调节糖酵解的机制。
通过对 252 例 GC 及其正常相邻组织的免疫组织化学染色，研究 FOXO4 蛋白的表达。我们在 GC 细胞系中恢复或沉默 FOXO4 表达，以探讨其潜在机制。
GC 中 FOXO4 表达下调。单因素和多因素生存分析验证了 FOXO4 表达缺失是总生存（P<0.05）和无病生存（P<0.05）的独立预后预测因子。恢复 FOXO4 表达显著降低了 GC 细胞的糖酵解率，而沉默 FOXO4 表达则增强了糖酵解率。FOXO4 表达与小鼠模型和患者样本中的最大标准化摄取值呈负相关。机制上，FOXO4 与糖酵解酶乳酸脱氢酶（LDHA）A 启动子结合，并以剂量依赖性方式使其失活（P<0.05）。最后，我们确定 FOXO4 是缺氧诱导因子（HIF）-1α的转录靶标，HIF-1α在缺氧反应中起核心作用。
我们的数据表明，FOXO4 在 GC 中糖酵解的调节中发挥关键作用，破坏 HIF-1α-FOXO4-LDHA 轴可能是 GC 的一种有前途的治疗策略。
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