Abstract
The Forkhead box M1 (FOXM1) transcription factor plays crucial roles in the initiation and progression of various malignancies, including hepatocellular carcinoma (HCC). However, the mechanism by which FOXM1 regulates cancer metabolism remains unclear. In the present study, overexpression and RNA interference (RNAi) approaches were used to investigate the role of FOXM1 in the regulation of glycolysis invitro. Luciferase reporter assays were used to explore the transcriptional regulation of the glucose transporter1 (GLUT1) promoter by FOXM1. Then, immunohistochemical staining was used to examine the expression of FOXM1 and GLUT1 in 100paired HCC and adjacent non-cancerous liver tissues. Chi-square test and logistic regression analysis were performed to evaluate the association between FOXM1 and GLUT1 expression with clinicopathological characteristics. Our data showed that FOXM1 promoted glycolysis in the HCC cells. FOXM1 knockdown significantly reduced the expression of GLUT1 among key glycolysis-related molecules in the different HCC cell lines. Glucose uptake and lactate production assay showed that FOXM1 positively regulated glycolysis based on GLUT1 expression. Moreover, FOXM1 overexpression increased and knockdown decreased GLUT1 expression. Luciferase reporter assays showed that the -206 to -199bp region of the GLUT1 promoter is important for FOXM1 to enhance GLUT1 promoter activity. The results of the IHC analysis showed that the protein expression of FOXM1 and GLUT1 was closely related to the tumor histological grade and TNM stage. In addition, GLUT1 expression was also related to microvascular invasion. In conclusion, overexpression of FOXM1 and GLUT1 may play critical roles in HCC. FOXM1 promotes HCC glycolysis by transactivating GLUT1 expression.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent neoplasms and the second leading cause of cancer-related mortality worldwide [1]
Among these key glycolysis-related molecules, we found that only glucose transporter 1 (GLUT1) mRNA expression was significantly downregulated in both the HepG2 and MHCC-97H hepatocellular carcinoma (HCC) cell lines when Forkhead box M1 (FOXM1) was knocked down by shRNA (Fig. 1A and B)
To further confirm the effect of FOXM1 on GLUT1 expression and HCC glycolysis, we assessed the correlation of FOXM1 expression with GLUT1 expression, glucose uptake and lactate production in 4 different HCC cell lines
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent neoplasms and the second leading cause of cancer-related mortality worldwide [1]. The underlying mechanisms that promote the pathogenesis of this deadly disease must be further investigated. Metabolic reprogramming has long been linked to cancer. One of the classical theories of metabolic abnormality in tumors is the Warburg effect, which describes increased glycolysis even under normal oxygen conditions [4]. The shift of the metabolic pathway from oxidative phosphorylation to glycolysis is more rapid to meet the demands necessary for the process of tumor progression. It is inefficient to generate ATP by consuming units of glucose under glycolysis conditions [5]. The glucose transporter 1 (GLUT1) isoform is a key rate-limiting protein in the transport of glucose and is overexpressed in HCC [6]. The mechanism underlying increased glycolysis by targeting GLUT1 in HCC is unknown
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