Expression of FOXP1 and FOXO3a in extrahepatic cholangiocarcinoma and the implications in clinicopathological significance and prognosis.

Aims: Extrahepatic cholangiocarcinoma (EHCC) is a highly malignant tumor with poor prognosis and intrinsic resistance to cytotoxic agents. The molecular mechanisms associated with high malignancy and resistance to chemotherapy and radiotherapy have not been fully elucidated. This study investigated the clinicopathological significances of FOXP1 and FOXO3a expression in EHCC. Methods: We assayed FOXP1 and FOXO3a expressions in 100 EHCC, 30 peritumoral tissues, 10 adenoma and 15 normal biliary tract tissues using EnVision immunohistochemistry. Results: The positive rates of FOXP1 and FOXO3a proteins were significantly lower in EHCC tumors than in peritumoral tissues, adenoma, and normal bile tract tissues (P<0.05 or P<0.01). Adenoma and pericancerous tissues with negative FOXP1 and/or FOXO3a protein expressions exhibited atypical hyperplasia. The positive correlation was established between the expression of FOXP1 and FOXO3a in EHCC (P<0.01). The positive rates of FOXP1 and FOXO3a expression were significantly higher in cases with well differentiation, no metastasis in lymph node, no invasion to surrounding tissues and organs, TNM I + II stage and radical resection (p<0.05 or p<0.01). Kaplan-Meier survival analysis showed that EHCC patients with positive FOXP1 and FOXO3a expression survived significantly higher than patients with negative FOXP1 and FOXO3a expression, respectively (P<0.001). Cox multivariate analysis revealed that negative FOXP1 or FOXO3a expressions were independent poor prognostic factors in EHCC patients. The AUCs for FOXP1 and FOXO3a were 0.676 (95% CI: 0.589-0.763, PG0.001) and 0.652 (95% CI: 0.563-741, P=0.002), respectively. Conclusion: The present study indicates that negative FOXP1 and FOXO3a expressions are closely associated with the pathogenesis, clinical, pathological and biological behaviors, and poor prognosis in EHCC.