Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis-related molecules

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.

Liver X Receptor a Inhibits Osteosarcoma Cell Proliferation through Up-Regulation of FoxO1

“…At the molecular level, FoxO1 could up-regulate the cell-cycle inhibitors p21 and p27, while down-regulate the cell cycle regulator cyclinD1/2, consequently leading to G1/S cell-cycle arrest [18]. Indeed, FoxO1 expression or activity was reduced in several types of cancers, including gastric cancer, breast cancer and osteosarcoma [19,20,21,22,23]. …”

Deciphering the roles of FOXO1 in human neoplasms

“…Kim et al . studied human gastric carcinoma specimens and revealed that cytoplasmic pFOXO1 expression is positively correlated with the expression of several angiogenesis‐related proteins (HIF‐1α, NF‐κB), compared with normal gastric tissues, suggesting that reduced expression of cytoplasmic pFOXO1 but enhanced expression of nuclear FOXO1 is a potential pathway for cancer treatment …”

“…Kim et al studied human gastric carcinoma specimens and revealed that cytoplasmic pFOXO1 expression is positively correlated with the expression of several angiogenesis-related proteins (HIF-1a, NF-jB), compared with normal gastric tissues, suggesting that reduced expression of cytoplasmic pFOXO1 but enhanced expression of nuclear FOXO1 is a potential pathway for cancer treatment. 110 FOXO1 exerts antitumor actions via other mechanisms, including oxidative stress, autophagy and ubiquitination. Skp2, an oncogenic subunit of the Skp1/Cul1/F-box ubiquitin protein system (UPS), interacts with ubiquitinases and promotes the degradation of FOXO1.…”

Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

“…22 Contradictory to these inhibitory effects are recent reports linking high FOXO expression to poor prognosis and tumor-promoting activity in intestinal, neuronal, and hematological malignancies. [23][24][25][26][27][28][29] The emerging concept of context-specific functions of FOXO proteins in cancer is substantially supported and extended in a breast cancer study in which FOXO activation needs optimal balance in order to promote cancer progression. 30 In GC B-cell-derived non-HLs, nonsynonymous FOXO1 mutations, which disrupt the N-terminal AKT recognition motif around T24, are recurrent.…”