Abstract
BackgroundP21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies. PAK1 overexpression is associated with poor prognosis in some tumor types, including breast cancer, gastric cancer, and colorectal cancer. However, the expression and clinical relevance of PAK1 expression in human pancreatic cancer remains unknown.MethodsThe present study investigated the clinical and prognostic significance of PAK1 expression in pancreatic carcinoma. We examined and scored the expression of PAK1 by immunohistochemistry in 72 primary pancreatic carcinoma samples and 20 liver metastatic samples. The relationships between PAK1 and clinicopathological parameters and prognosis in primary and metastatic pancreatic cancer were analyzed.ResultsAmong the total 92 cases, primary pancreatic cancer samples had a significantly higher rate (38/72, 52.8%) of high PAK1 expression than liver metastatic samples (5/20, 25.0%) (P = 0.028). Among the 72 primary pancreatic cancer patients, high PAK1 expression was associated with younger age (P = 0.038) and moderately or well differentiated tumor (P = 0.007). Moreover, a positive relationship was found between high PAK1 expression and overall survival (OS) (P < 0.005). Patients with high PAK1 expression had a better OS than those with low PAK1 expression. Univariate and multivariate analysis by Cox regression including PAK1 and other prognostic pathological markers demonstrated high PAK1 immunostaining as a prognostic factor for survival in pancreatic cancer patients (P < 0.005).ConclusionsWe report for the first time that PAK1 is a novel prognostic marker for pathologically confirmed human pancreatic cancer. Reduced expression of PAK1 correlates with poor histological differentiation in pancreatic cancer.
Highlights
P21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies
p21-activated protein kinase 1 (PAK1) expression is higher in primary pancreatic cancer tissues than in metastatic tissues The clinical and pathological characteristics of patients with primary and metastatic pancreatic cancer are shown in Table 1 and Table 2
PAK1 protein expression was significantly higher in the 72 human primary pancreatic cancer tissues compared to the 20 liver metastatic tissues (Figure 1) as determined by IHC
Summary
P21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies. The p21-associated kinases (PAKs) were first discovered in a screen for proteins that interact with the small G-proteins Rac and Cdc in 1994 [6]. In group I PAKs, the p21binding domain (PBD) in the N-terminal domain binds Rac and Cdc to cause autophosphorylation of specific sites in the N-terminal inhibitory domain, leading to a conformational change that releases the autoinhibition and activates the kinase activity [7]. Group I PAKs contain a proline-rich region that is associated with binding to Nck, an adapter protein involved in the regulation of actin cytoskeletal dynamics [11]. Crystal structures of phosphorylated and active catalytic domains of all three group II PAKs reveal a monomeric conformation [12,13]
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