Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer

Abstract

Increased phosphorylation of FOXO1A, a FOXO transcription factor, has been implicated in several human cancers; however, it has not been studied in the gastric cancer to date. To determine the status of pFOXO1A expression in human gastric cancers and to determine its relationship with other tumor-associated proteins, we performed immunohistochemical staining on tissue array slides containing 272 human gastric carcinoma specimens. In non-neoplastic gastric mucosa, the expression of pFOXO1A was observed primarily in cells in the proliferative zone and in areas of intestinal metaplasia. In gastric carcinomas, the expression of pFOXO1A was observed in 230 (84.6%) out of 272 cases examined, and was positively correlated with the Ki-67-labeling index (P ¼ 0.026). The expression of pFOXO1A was higher in the early stages of pTNM (Po0.001), and was inversely correlated with the intestinal type by Lauren's classification (P ¼ 0.001), lymphatic invasion (P ¼ 0.017) and lymph node metastasis (Po0.001). Moreover, the expression of pFOXO1A was correlated with a longer patient survival (P ¼ 0.004). In addition, the expression of pFOXO1A was correlated with that of pAKT1 (Po0.001), PTEN (P ¼ 0.009), CDKN2A (P ¼ 0.012), APC (P ¼ 0.048), SMAD4 (Po0.001), CD82 (P ¼ 0.011), and BCL2 (P ¼ 0.011). In conclusion, our results showed that the expression of pFOXO1A is a frequent and early event in gastric tumorigenesis and that there is a significant correlation between pFOXO1A and better prognosis. Thus, our data suggest that the expression of pFOXO1A may serve as a valuable prognostic variable in gastric carcinoma and have significant implications for the development and application of targeted therapy.

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

“…To the best of our knowledge, this is the first study to demonstrate the correlation between FOXO1 and chemoresistance in gastric cancer cells. We have previously shown that phosphorylated FOXO1 is overexpressed in gastric cancer specimens and that FOXO1 inactivation is related to better prognosis of gastric cancer patients [18]. Although FOXO proteins, especially FOXO1 and FOXO3, have been reported to be related to chemoresistance in various cancer cells [8][9][10][19][20][21], their involvement in chemoresistance of gastric cancer cells has not been reported.…”

Protein predictive signatures for lymph node metastasis of gastric cancer

“…For example, VCAM-1, MMP-9 and uPA were up-regulated in gastric cancer and closely related to the metastasis, [17][18][19] while FKHR and connexin43 were down-regulated in gastric cancer. 20,21 Some of the dysregulated proteins were reported in other cancers but not in gastric cancer. For example, Pax-2 was up-regulated in renal cell cancer 22 and WT1 was down-regulated in lung cancer.…”

Forkhead box-O transcription factor: critical conductors of cancer's fate

“…The PI3K/Akt signalling pathway has emerged as a central mitogenic pathway in various types of mammalian cancer (Zbuk & Eng 2007) and there is amble evidence for a direct correlation between PI3K/Akt activation and FOXO inactivation in cancers (Kim et al 2007, Yip et al 2008.…”