Impact of prospero homeobox-1 on tumor cell behavior and prognosis in colorectal cancer.

Prospero homeobox 1 (PROX1) is up-regulated in colorectal cancer and plays an oncogenic role. In the present study, we sought to investigate the impact of PROX1 on oncogenic processes and to assess the prognostic value of PROX1 expression in colorectal cancer. A small interfering RNA or pcDNA6-myc vector was used to control PROX1 gene expression in colorectal cancer DLD1 and SW480 cell lines. The expression of PROX1 in colorectal cancer tissues was investigated by immunohistochemistry. Angiogenesis, lymphangiogenesis, and tumor cell proliferation were assessed by analyzing the expression of respective markers of these phenomena, CD34, D2-40, and Ki-67 after immunohistochemical staining. PROX1 knockdown decreased both umbilical vein endothelial cell invasion and tube formation, down-regulated the expression of VEGF-A and HIF-1α, and up-regulated the expression of angiostatin. Lymphatic endothelial cell invasion and tube formation as well as the expression of VEGF-C were also suppressed by PROX1 knockdown. PROX1 knockdown suppressed tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In contrast, PROX1 overexpression enhanced tumor cell angiogenesis, lymphangiogenesis, proliferation, migration, invasion, and epithelial-mesenchymal transition. Levels of phosphorylated Akt, GSK3β, and MAPK were decreased by PROX1 knockdown and increased by PROX1 overexpression. PROX1 expression positively correlated with tumor size, extent of differentiation, lymphovascular invasion, depth of invasion, lymph node metastasis, stage, and poor survival. The mean microvessel density and Ki-67 labeling index values of PROX1-positive tumors were significantly higher than those of PROX1-negative tumors. However, there was no significant correlation between PROX1 expression and lymphatic vessel density. These results indicate that PROX1 influences tumor progression in colorectal cancer by regulating angiogenesis and tumor cell proliferation.