Abstract
The results of a cDNA array revealed that protocadherin gamma subfamily A, 9 (PCDHGA9) was significantly decreased in SGC-7901 gastric cancer (GC) cells compared with GES-1 normal gastric cells and was strongly associated with the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad2/3 signaling pathway. As a member of the cadherin family, PCDHGA9 functions in both cell–cell adhesion and nuclear signaling. However, its role in tumorigenicity or metastasis has not been reported. In the present study, we found that PCDHGA9 was decreased in GC tissues compared with corresponding normal mucosae and its expression was correlated with the GC TNM stage, the UICC stage, differentiation, relapse, and metastasis (p < 0.01). Multivariate Cox analysis revealed that PCDHGA9 was an independent prognostic indicator for overall survival (OS) and disease-free survival (DFS) (p < 0.01). The effects of PCDHGA9 on GC tumor growth and metastasis were examined both in vivo and in vitro. PCDHGA9 knockdown promoted GC cell proliferation, migration, and invasion, whereas PCDHGA9 overexpression inhibited GC tumor growth and metastasis but induced apoptosis, autophagy, and G1 cell cycle arrest. Furthermore, PCDHGA9 suppressed epithelial–mesenchymal transition (EMT) induced by TGF-β, decreased the phosphorylation of Smad2/3, and inhibited the nuclear translocation of pSmad2/3. Our results suggest that PCDHGA9 might interact with β-catenin to prevent β-catenin from dissociating in the cytoplasm and translocating to the nucleus. Moreover, PCDHGA9 overexpression restrained cell proliferation and reduced the nuclear β-catenin, an indicator of Wnt/β-catenin pathway activation, suggesting that PCDHGA9 negatively regulates Wnt signaling. Together, these data indicate that PCDHGA9 acts as a tumor suppressor with anti-proliferative activity and anti-invasive ability, and the reduction of PCDHGA9 could serve as an independent prognostic biomarker in GC.
Highlights
Gastric cancer (GC) is the third leading cause of cancerrelated mortality worldwide and the fifth common cause of cancer globally[1]
We used cell functional assays in vitro and in vivo to reveal the anti-carcinogenic mechanisms of PCDHGA9 in GC and explore its prognostic value. These findings provide the first evidence that PCDHGA9 acts as a tumor suppressor inducing tumor cell apoptosis, autophagy, and cell cycle arrest and reducing the epithelial–mesenchymal transition (EMT) process in human GC
PCDHGA9 expression is reduced in human GC tissue The results of real-time PCR indicated that the messenger RNA level of PCDHGA9 was significantly decreased in 38 (80.85%) GC samples compared with that in the nonmalignant samples (Fig. 2a)
Summary
Gastric cancer (GC) is the third leading cause of cancerrelated mortality worldwide and the fifth common cause of cancer globally[1]. A deeper understanding of the Official journal of the Cell Death Differentiation Association. Weng et al Cell Death and Disease mechanisms underlying GC development and metastasis may lead to innovative therapeutic strategies. Pcdhs are the largest mammalian subgroup of the cadherin superfamily. Little information is available about the association between Pcdhs and tumorigenesis or nuclear signaling. Β-catenin shows reduced binding to cadherins, mediating their impact in gene transcription. Cadherins might function as competitors of nuclear signaling[3]. The aim of the present study was to examine whether PCDHGA9 suppresses tumor cell proliferation via interaction with β-catenin that disrupt canonical Wnt signaling in GC
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