Gastrointestinal Factor GDDR Attenuates Epithelial-Mesenchymal Transition in Gastric Cancer via Inhibiting AKT Signal.

Abstract

The gastric dramatic down-related gene (GDDR) is an abundantly expressed secretory protein in normal gastric epithelia, while its expression is distinctly decreased in gastric cancer. However, the role of GDDR in gastric cancer remains poorly understood. This study aims to detect the expression and clinical significance of GDDR in gastric cancer and investigate its effects on epithelial-mesenchymal transition. The expression of GDDR in gastric cancer was examined by immunohistochemistry, immunoblotting, and Western blotting. The relationships between GDDR expression and clinicopathological factors were evaluated. The effects of GDDR on epithelial-mesenchymal transition of gastric cancer cells were investigated in vitro. GDDR was absent in gastric cancer tissue or dramatically downregulated in gastric cancer cell lines. Loss of GDDR expression in gastric cancer was strongly correlated with clinicopathological factors, such as tumor differentiation (p=0.037), T stage (p<0.001), lymph node metastasis (p=0.008) and TNM stage (p<0.001). Patients with decreased GDDR expression presented shortened overall survival (p=0.033). Functional studies demonstrated that GDDR elevation augmented cell-cell adhesion and suppressed cell motility, concomitant with increased expression of E-cadherin and decreased expression of β-catenin and vimentin. Conversely, GDDR depletion increased cell motility, concomitant with decreased expression of E-cadherin and increased expression of β-catenin and vimentin. Moreover, GDDR had an inhibitory effect on PI3K/Akt signaling pathway. Our findings suggested that GDDR expression was significantly associated with the progression of gastric cancer and GDDR may function as a tumor suppressor via inhibiting the epithelial-mesenchymal transition.