Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer.
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=0.026). The expression of pFOXO1A was higher in the early stages of pTNM (P<0.001), and was inversely correlated with the intestinal type by Lauren's classification (P=0.001), lymphatic invasion (P=0.017) and lymph node metastasis (P<0.001). Moreover, the expression of pFOXO1A was correlated with a longer patient survival (P=0.004). In addition, the expression of pFOXO1A was correlated with that of pAKT1 (P<0.001), PTEN (P=0.009), CDKN2A (P=0.012), APC (P=0.048), SMAD4 (P<0.001), CD82 (P=0.011), and BCL2 (P=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.
Kim
Ji Hun
JH
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Kim
Min Kyu
MK
Lee
Hee Eun
HE
Cho
Sung Jin
SJ
Cho
Yu Jin
YJ
Lee
Byung Lan
BL
Lee
Hye Seung
HS
Nam
Seon Young
SY
Lee
Jae-Seon
JS
Kim
Woo Ho
WH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000032:analysis*; D051549:Glutathione S-Transferase pi / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D013482:Superoxide Dismutase / Q000032:analysis; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis
D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D013482:Superoxide Dismutase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt