RRC ID 38418
Author Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, So KK, Wu K, Fan D, Yu J, Sung JJ, To KF.
Title Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis.
Journal Clin Cancer Res
Abstract PURPOSE:Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed to investigate the functional role of YAP1 in tumorigenesis of gastric cancer.
EXPERIMENTAL DESIGN:YAP1 expression in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray.
RESULTS:YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P < 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor-induced c-Fos expression in gastric cancer cells.
CONCLUSIONS:Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer.
Volume 17(8)
Pages 2130-9
Published 2011-4-15
DOI 10.1158/1078-0432.CCR-10-2467
PII 1078-0432.CCR-10-2467
PMID 21346147
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Adult Aged Aged, 80 and over Animals Base Sequence Blotting, Western Cell Line, Tumor Cell Nucleus / metabolism* Extracellular Signal-Regulated MAP Kinases / metabolism Female Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Male Mice Mice, Inbred BALB C Mice, Nude Middle Aged Neoplasms, Experimental / genetics Neoplasms, Experimental / metabolism Neoplasms, Experimental / pathology Oncogenes / genetics Phosphoproteins / genetics Phosphoproteins / metabolism* Prognosis RNA Interference Reverse Transcriptase Polymerase Chain Reaction Stomach Neoplasms / genetics Stomach Neoplasms / metabolism* Stomach Neoplasms / pathology Transcription Factors
IF 8.911
Times Cited 156
Human and Animal Cells