Decreased TOB1 expression and increased phosphorylation of nuclear TOB1 promotes gastric cancer.

ABSTRACT

TOB1, a member of the BTG/TOB protein family, inhibits tumor cell proliferation. We previously observed down-regulation and phosphorylation of TOB1 in gastric cancer (GC). Here, we examined the subcellular distribution and clinical significance of TOB1 expression and phosphorylation in GC. Immunohistochemical analysis of 341 primary GC and corresponding normal gastric tissue samples demonstrated that nuclear TOB1 expression was lower in GC than normal tissue (80.4% vs. 92.4%), and decreased nuclear TOB1 expression correlated with high TNM stage. By contrast, phosphorylation of nuclear TOB1 was higher in GC than normal gastric tissue (66.0% vs. 36.4%), and was associated with poorly differentiated and high TNM stage tumors. Patients with intestinal type GC and increased nuclear TOB1 phosphorylation had poor overall survival. Multivariate survival analysis indicated the nuclear concentration of phosphorylated TOB1 was an independent prognostic factor for intestinal type GC. Overexpression of TOB1 containing mutations in its nuclear export signal inhibited GC cell proliferation, migration, and invasion compared to cells expressing TOB1 with the nuclear localization signal. Thus, decreased TOB1 expression and increased phosphorylation of nuclear TOB1 is associated with aggressive tumor behavior and poor prognosis in intestinal type GC. Additionally, TOB1 nuclear retention is critical for its anti-proliferative activity.