Abstract
Purpose: The molecular, cellular and animal studies have established that overexpressed proline-directed protein kinase FA (PDPK FA) is essential for the development of tumorigenesis, invasion, and metastasis of human cancer cells. However, the prognostic role of PDPK FA in cancer patients remains largely unknown. The present thesis was comprehensively to examine association of PDPK FA expression with cancer progression and patient survival. Patients and Methods: PDPK FA expression in the resected tumors of 275 cancer patients, including 167 head and neck squamous cell carcinoma (HNSCC) patients, 74 colorectal cancer patients, and 34 esophageal cancer patients was analyzed by immunohistochemistry. Highly condensed nuclear PDPK FA exhibited in tumor cells was used as the major scoring parameter for positive PDPK FA expression. Survival analysis was used to analyze the data. Results: The frequency of positive PDPK FA expression was 41.3% (67/167) in HNSCC. Patients with positive PDPK FA showed poorer disease-free survival (DFS) and overall survival (OS) (P<0.001 for both). Cox multivariate regression analysis further established PDPK FA as the strongest independent prognosticator for cancer progression and patient survival in HNSCC (HR 3.063, 95% CI 1.884-4.981, P<0.001 for DFS and HR 4.192, 95% CI 2.396-7.332, P<0.001 for OS). Further, in the combination analysis with independent prognostic factor on the survival data, PDPK FA appeared to play a determinant, instructional and predominant role superior to the current powerful TNM staging system in prognostic prediction. Finally, logistic analysis showed that established PDPK FA is a very powerful prognostic indicator of response to adjuvant therapy in HNSCC (OR 12.581, 95% CI 4.807-32.932, P<0.001). Besides, we combined the other two different types of cancers (colorectal cancer and esophageal cancer) to analyze. The frequency of positive PDPK FA expression was 41.8% (115/275). Patients with positive PDPK FA showed poorer disease-free survival (DFS) and overall survival (OS) (P<0.001 for both). Cox multivariate regression analysis further established PDPK FA as the strongest independent prognosticator for cancer progression and patient survival (HR 3.980, 95% CI 2.658-5.960, P<0.001 for DFS and HR 5.815, 95% CI 3.649-9.267, P<0.001 for OS). Further, in the combination analysis with independent prognostic factor on the survival data, PDPK FA appeared to play a determinant, instructional and predominant role superior to the current powerful TNM staging system in prognostic prediction. Finally, logistic analysis showed that established PDPK FA is a very powerful prognostic indicator of response to adjuvant therapy (OR 11.911, 95% CI 5.465-25.958, P<0.001). Conclusion: In consistence with its multisubstrate/multifunctional PDPK nature essential for the development of highly malignant phenotypes, the present human study indicates that PDPK FA is a new signal transducing molecule for prediction of cancer progression and response to adjuvant therapy. Together with the previous molecular, cellular and animal studies, this thesis establishes PDPK FA as a new and common promising target for the strategic development of reliable and accessible prognostic and therapeutic modalities for more efficacious treatment in different types of cancers.