Abstract
BackgroundAlthough FOXO transcription factors may have an anti-angiogenic role, little is known about their role in tumor angiogenesis. The present study was performed to investigate the correlation between the constitutive expression of phosphorylated FOXO1 (pFOXO1) and angiogenesis in gastric cancer.MethodsImmunohistochemistry was performed on tissue array slides containing 272 gastric carcinoma specimens, and the correlations between the cytoplasmic pFOXO1 expression in gastric cancer cells and CD34-immunopositive microvessel area (MVA) or the expressions of angiogenesis-related molecules were analyzed. In vitro analyses with Western blotting and semiquantitative reverse transcription-polymerase chain reaction were performed using the stable SNU-638 gastric cancer cell line transfected with lentivirus-delivered FOXO1 short hairpin RNA.ResultsThe cytoplasmic expression of pFOXO1 in tumor cells was observed in 85% of gastric carcinoma cases, and was found to be positively associated with higher MVA (P = 0.048). Moreover, pFOXO1 expression was positively correlated with the expressions of several angiogenesis-related proteins, including hypoxia inducible factor-1α (HIF-1α, P = 0.003), vessel endothelial growth factor (P = 0.004), phosphorylated protein kinase B (P < 0.001), and nuclear factor-κB (P = 0.040). In contrast, the expression of pFOXO1 was not correlated with that of phosphorylated signal transducer and activator of transcription 3 or β-catenin. In addition, cell culture experiments showed that FOXO1 suppression increased the mRNA and protein expressions of HIF-1α.ConclusionOur results suggest that pFOXO1 expression in cancer cells plays a role in gastric cancer angiogenesis via mechanisms involving various angiogenesis-related molecules. Animal experiments are needed to confirm the anti-angiogenic role of FOXO1 in human gastric cancer.
Highlights
FOXO transcription factors may have an anti-angiogenic role, little is known about their role in tumor angiogenesis
Expressions of phosphorylated FOXO1 (pFOXO1) and angiogenesis-related proteins in gastric cancer specimens Immunohistochemical staining was used to investigate the correlation between pFOXO1 expression and angiogenesis in gastric cancer
We found that cytoplasmic pFOXO1 expression in gastric cancer cells was positively correlated with microvessel area (MVA) (P = 0.048), suggesting that FOXO1 is involved in gastric tumor angiogenesis
Summary
FOXO transcription factors may have an anti-angiogenic role, little is known about their role in tumor angiogenesis. FOXOs are emerging as an important family of proteins that are implicated in the regulations of several biological processes, including the stress resistance, metabolism, cell cycle, apoptosis, and DNA repair [3]. Dysregulations of these proteins may lead to disease such as cancer [4]. Previous studies have shown that the anti-tumor activity of FOXOs comes from their pro-apoptotic [6,7,8] and inhibitory cell cycle effects [3,9]. The role of FOXOs in tumor angiogenesis has not been investigated
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