Overexpression of forkhead box M1 and urokinase-type plasminogen activator in gastric cancer is associated with cancer progression and poor prognosis

Abstract

Forkhead box M1 (FOXM1) and urokinase-type plasminogen activator (uPA) are overexpressed and associated with the pathogenesis of multiple types of human malignancy. The aims of the present study were to investigate FOXM1 and uPA expression levels in human gastric cancer using tissue microarray techniques; determining their association with clinicopathological characteristics as well as their prognostic value. Tissue microarray blocks, comprising 436 gastric cancer cases and 92 non-cancerous adjacent normal gastric tissues, were analyzed for FOXM1 and uPA protein expression levels using immunohistochemistry. The results were analyzed statistically in association with various clinicopathological characteristics and overall survival rates. FOXM1 and uPA were detected in 78.67 (343/436) and 83.26% (363/436) of cancer samples, respectively. FOXM1 and uPA were not expressed in the 92 normal gastric tissue samples. In gastric cancer, FOXM1 and uPA levels were associated with tumor size, depth of invasion, tumor-node-metastasis (TNM) stage, lymph node metastasis, vessel invasion and distant metastases. The overall survival rate was significantly decreased in patients expressing FOXM1 and uPA compared with FOXM1and uPA-negative patients. Cox’s multivariate analysis revealed that age, depth of invasion and expression levels of FOXM1 and uPA are independent predictors of survival in patients with gastric cancer. These results indicated that increased FOXM1 and uPA expression levels are associated with the invasive and metastatic processes in human gastric cancer, and inversely associated with patient prognosis. Therefore, FOXM1 and uPA may serve as novel prognostic markers independent of, but supplementing, the TNM staging system.