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Mol Oncol. 2017 Sep;11(9):1208-1224. doi: 10.1002/1878-0261.12089. Epub 2017 Jun 22.

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β-catenin signaling pathway.

Author information

1
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
2
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
3
Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.

Abstract

Gastric cancer (GC) represents the fourth most common malignant neoplasm and the second leading cause of cancer death. Despite therapeutic advances in recent decades, the clinical outcome remains dismal owing to the fact that most patients with GC show advanced disease at diagnosis and current chemotherapy only confers a modest survival advantage. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression would aid in early diagnosis and provide a rational design for targeted therapies in selected patients with advanced GC, to improve their outcome. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the main enzyme that can degrade asymmetric dimethylarginine, an endogenous nitric oxide synthase (NOS) inhibitor. Increased DDAH1 expression and NO production have been linked to multiple pathological conditions including cancer. However, the prognostic significance of DDAH1 in patients with GC and its function in GC progression remain undefined. In this study, we found that downregulation of DDAH1 was frequently detected in GC tissues and strongly correlated with more aggressive phenotypes and poor prognosis. Functional assays confirmed that forced expression of DDAH1 in the GC cells suppressed cell migration and invasion in vitro, as well as metastatic potential in vivo. DDAH1 overexpression inhibited the epithelial-mesenchymal transition process by increasing β-catenin degradation through the attenuation of Wnt/GSK-3β signaling. In contrast, knockdown of DDAH1 produced the opposite effect. These findings suggest that DDAH1 functions as a tumor suppressor in GC and may be exploited as a diagnostic and prognostic biomarker for GC.

KEYWORDS:

Wnt/β-catenin; dimethylarginine dimethylaminohydrolase 1; epithelial-mesenchymal transition; gastric cancer; tumor suppressor

PMID:
28580735
PMCID:
PMC5579338
DOI:
10.1002/1878-0261.12089
[Indexed for MEDLINE]
Free PMC Article

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