Study summary · research use only
Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study, using human gastric cancer (GC) tissue samples, cell lines, and mouse models, examined how FOXO4 regulates glycolysis under hypoxia. The authors assessed FOXO4 protein expression by immunohistochemical staining of 252 GC and adjacent normal tissue samples, and restored or silenced FOXO4 expression in GC cell lines. They report that FOXO4 was downregulated in GC and was an independent prognostic predictor for overall and disease-free survival. Restoring FOXO4 expression reduced glycolysis in GC cells, while silencing it increased glycolysis. FOXO4 was reported to bind the LDHA promoter and inactivate its activity in a dose-dependent manner, and to be a transcriptional target of HIF-1α. The authors describe disrupting the HIF-1α-FOXO4-LDHA axis as a possible therapeutic strategy for GC.
Abstract
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.
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