Identifying an effective therapeutic target is pivotal in the treatment of gastric cancer. In this study, we investigated the expression of p75 neurotrophin receptor (p75NTR) in gastric cancer and the impact of its alteration on tumor growth. p75NTR expression was absent or significantly decreased in 212 cases of gastric cancers compared with the normal gastric mucosa (P < .05). Moreover, p75NTR expression was also lost or significantly decreased in various human gastric cancer cell lines. p75NTR inhibited in vitro growth activities and caused dramatic attenuation of tumor growth in animal models by induction of cell cycle arrest. Upregulation of p75NTR led to downregulation of cyclin A, cyclin D1, cyclin E, cyclin-dependent kinase 2, p-Rb, and PCNA, but to upregulation of Rb and p27 expressions. Conversely, downregulating p75NTR with specific siRNA yielded inverse results. The rescue of tumor cells from cell cycle progression by a death domain-deleted dominant-negative antagonist of p75NTR (Deltap75NTR) showed that the death domain transduced antiproliferative activity in a ligand-independent manner and further demonstrated the inhibitive effect of p75NTR on growth in gastric cancer. Therefore, we provided evidence that p75NTR was a potential tumor suppressor and may be used as a therapeutic target for gastric cancer.

Hypoxia inducible factor-1alpha (HIF-1alpha) was well correlated with carcinogenesis and tumor progression in many kinds of cancer. In this study, high expression of HIF-1alpha was found in 37 of the 72 (51.39%) tumor specimens, and significantly correlated with venous invasion and lymphonode invasion. Patients with high expression of HIF-1alpha had a significantly shorter overall survival rate and disease-free survival rate than those with low expression. Multivariate analysis showed high HIF-1alpha expression was a borderline independent factor of overall survival. HIF-1alpha expression was also found to be significantly correlated with the expression of hepatitis B virus X protein (HBx), and over-expressed HBx upregulated HIF-1alpha protein expression in vitro. These results suggested that HIF-1alpha, which was partially regulated by HBx, might be a prognostic marker of HBV-related HCC patients.

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