Abstract
BackgroundLow expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear.Materials and methodsThe effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1.ResultsFOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2.ConclusionFOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.
Highlights
Colorectal cancer (CRC) is one of the most common malignant cancers worldwide [1]
Low FOXE1 expression is associated with poor prognosis of colorectal cancer (CRC) To investigate the prognostic value of FOXE1 in CRC cases, we tested its protein level in both CRC and paired normal tissues in Tissue microarray (TMA) by IHC staining, which showed FOXE1 was highly expressed in normal mucosa compared with CRC tissues (Fig. 1a and b)
Correlation analysis showed that low expression of FOXE1 was significantly associated with poor clinicopathological features including advanced tumor stage and venous invasion (Additional file 3: Table S1). 17.9% of patents with low FOXE1 expression were diagnosed as metastatic CRC while only 5.2% of patents with high FOXE1 expression were stage IV disease (Additional file 3: Table S1)
Summary
Colorectal cancer (CRC) is one of the most common malignant cancers worldwide [1]. Cancers share a common phenotype of uncontrolled cell proliferation and must efficiently generate the energy and macromolecules required for cellular growth [4, 5]. The Warburg effect is the first example of metabolic reprogramming. Many studies have confirmed that oncogenes and tumor suppressors, such as hypoxia-inducible factor-1a, Myc, p53, PTEN, and Ras can reprogram energy metabolism in cancer cells [8,9,10,11]. The mechanisms accounting for the activation of the Warburg effect and progression of CRC remains blurry. Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients.
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