Prognostic Importance and Therapeutic Implications of PAK1, a Drugable Protein Kinase, in Gastroesophageal Junction Adenocarcinoma

Abstract

Gastroesophageal junction (GEJ) adenocarcinoma is a lethal cancer with rising incidence, yet the molecular biomarkers that have strong prognostic impact and also hold great therapeutic promise remain elusive. We used a data mining approach and identified the p21 protein-activated kinase 1 (PAK1), an oncogene and drugable protein kinase, to be among the most promising targets for GEJ adenocarcinoma. Immunoblot analysis and data mining demonstrated that PAK1 protein and mRNA were upregulated in cancer tissues compared to the noncancerous tissues. Immunohistochemistry revealed PAK1 overexpression in 72.6% of primary GEJ adenocarcinomas (n = 113). A step-wise increase in PAK1 levels was noted from paired normal epithelium, to atypical hyperplasia and adenocarcinoma. PAK1 overexpression in tumor was associated with lymph node (LN) metastasis (P<0.001), advanced tumor stage (P<0.001), large tumor size (P = 0.006), residual surgical margin (P = 0.033), and unfavorable overall survival (P<0.001). Multivariate analysis showed PAK1 overexpression is an independent high-risk prognostic predictor (P<0.001). Collectively, PAK1 is overexpressed during tumorigenic progression and its upregulation correlates with malignant properties mainly relevant to invasion and metastasis. PAK1 expression could serve as a prognostic predictor that holds therapeutic promise for GEJ adenocarcinoma.

Personalizing risk stratification by addition of PAK1 expression to TNM staging: Improving the accuracy of clinical decision for gastroesophageal junction adenocarcinoma

“…In this study, we demonstrate that IHC‐based measurement of PAK1 expression in the PT provides a readily quantifiable biomarker for prognosis of GEJA in the absence of adequate lymphadenectomy. We previously reported that PAK1 is a prognostic biomarker for GEJA . In this report, we provide bioinformatics evidence that PAK1 is closely associated with metastasis in GEJA (Fig.…”

“…IHC for PAK1 was performed on thin (4 μm) tissue sections cut from surgical specimens fixed in 10% buffered formalin and embedded in paraffin. After deparaffinization, rehydration, endogenous peroxidase blocking and antigen retrieval according to previously described procedures, the sections were incubated with a rabbit polyclonal antibody against human PAK1 (1:100; Cell Signaling, Beverly, MA) overnight at 4°C. PAK1 cytoplasmic staining was evaluated by standard light microscopy.…”

“…Our previous work identified p21 protein (Cdc42/Rac)‐activated kinase 1 (PAK1) as a prognostic biomarker, the overexpression of which is associated with poor survival in GEJA . PAK1 is a kinase that modulates downstream signaling events involved in cytoskeletal reorganization, cell motility and epithelial–mesenchymal transition .…”

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

“…Because PAK1 has been recognized as a potential pharmacological molecular target, the clinical pipeline of molecular therapy targeting PAK1 has been growing (21)(22)(23). Our previous studies and those of other investigators demonstrated that PAK1 is up-regulated in cancers of the gastrointestinal tract, including GC (23)(24)(25)(26)(27)(28). Intriguingly, PAK1 also activates the inflammatory signaling induced by H. pylori infection in epithelial cells, further linking PAK1 to human GC pathogenesis (29).…”

Dysregulation of PAK1 Is Associated with DNA Damage and Is of Prognostic Importance in Primary Esophageal Small Cell Carcinoma

“…PAK1 acts as a convergence point in a composite oncogenic signaling pathway [ 18 ] and its dysregulation possibly influences oncogenic transformation and survival. Several clinical [ 19 , 20 ] and functional studies have implicated PAK1 in tumor metastasis. Studies confirmed that inhibition of PAK1 in human tumors and in vivo tumor models resulted in an anti-tumoral effect [ 15 ].…”