FOXO1 Downregulation Correlates with Progression of Esophageal Intraepithelial Neoplasia

Abstract

Background: Forkhead transcription protein 1 (FOXO1) is an important transcriptional regulator of cell proliferation and is considered essential for tumor growth and progression. However, the function of FOXO1 in esophageal cancer remains unclear. Esophageal squamous intraepithelial neoplasia (ESIN) has been widely recognized as a precursor lesion for esophageal squamous cell carcinoma (ESCC). Early detection offers the best prognosis for esophageal squamous cell carcinoma. The differentiation of squamous dysplasia from reactive change and the classification of ESIN into high-grade (HGIEN) or low-grade (LGIEN) are sometimes subjective and challenging. In this study, we sought to evaluate the FOXO1 expression in endoscopically biopsied esophageal cases and compare its expression with those of p AKT1, Ki67 and p53 to detect where is the lesion stand in the scale from normal mucosa to HGIEN in order not to miss prone cancer cases. Methodology and results: Immunohistochemical staining was performed on 99 formalin-fixed, paraffin embedded blocks of endoscopic esophageal samples. Out of them, 44 samples were ESIN and 33 samples were ESCC, further, for comparison, 22 samples of reactive hyperplastic, non-dysplastic esophageal mucosa. The current study showed a significant stepwise decrease in the FOXO1 expression as well as increased expression of p AKT1, ki67 and P53 from the progression of LGIEN to HGIEN to ESCC. HGIEN and ESCC strongly associated with low FOXO1 expression. On the other hand, higher expression of p AKT1, ki67 and p53 was more associated with HGIEN and ESCC (all are P: 0.001). Conclusions: This study demonstrated stepwise under-expression of FOXO1 in the progression of esophageal squamous carcinogenesis so that immunohistochemical assessment of this marker might provide a useful adjunct tool for differential diagnosis between LGIEN and HGIEN as well as could be used in targeting therapy.