Association of Proline-Directed Protein Kinase F-a with Tumorigenesis, Invasion, and Poor Prognosis of Human Colon Carcinoma

Abstract

BACKGROUND. Initial studies revealed that the multisubstrate proline- directed protein kinase F-A (PDPK F-A) is overexpressed in various types of human carcinomas relative to normal controls. Suppression of overexpressed PDPK F-A inhibits the growth of cancer cells, suggesting a role of this PDPK in human malignancy. In this study, we combine immunohistologic, molecular, cellular, animal, and clinicopathologic studies to demonstrate an essential and critical role of PDPK F-A in progression and poor prognosis of human colon carcinoma. METHODS. The stable antisense clones of human colon carcinoma cells with specific suppression of PDPK F-A were established for tumorigenesis and invasion studies. In immunohistologic and clinicopathologic studies, the expression and localization of PDPK F-A were analyzed by immunohistochemical staining of the specimens obtained from human colon carcinoma patients with Dukes Stage B/C. RESULTS. Initial molecular and cellular studies revealed that the antisense clone of colon carcinoma cells (COLO-205) with specific suppression of PDPK F-A dramatically lost capabilities of adhesion, chemotaxis, and invasion when compared with the parental or control- transfected colon carcinoma cells. This is the first indication of an association of overexpressed PDPK F-A with colon carcinoma progression. In agreement with this notion, the in vivo study also revealed that the mice injected with the antisense clone with low-level PDPK F-A only developed very small tumors (< 0.5 cm(3)) even after a 6- week observation. This is in contrast to the parental or control- transfected cells that developed large tumors (> 5 cm(3)) under identical conditions. Pathologic evaluation revealed invasion to the muscle layer in all tumors formed by the parental cells. In contrast, there was no sign of invasion in mice injected with the antisense clone, confirming an essential role of PDPK F-A in colon carcinoma progression. Clinicopathologic study also revealed that PDPK F-A is preferentially overexpressed in the invasive area of colon carcinomatous tissues and overexpression of PDPK F-A is statistically and closely correlated with venous/lymphatic infiltration, lymph node metastasis, and poor prognosis of colon carcinoma patients with Dukes Stage B/C. CONCLUSIONS. The results demonstrate an essential and critical role of overexpressed PDPK F-A in progression and poor prognosis of colon carcinoma patients. Suppression of overexpressed PDPK F-A may provide a new powerful adjuvant approach to prevent human colon carcinoma progression and poor prognosis after surgery and chemotherapy.