Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt‐mediated HIF‐1α up‐regulation and MMP9 activation

Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein. OPN has been shown to facilitate the progression and metastasis of malignancies and has prognostic value in several types of cancer, including gastric cancer. However, the functional mechanism of OPN mediated metastatic growth in gastric cancer remains unclear. Here, using multiple in vitro and in vivo models, we report that OPN strongly promoted the progression and metastasis of gastric cancer. Immunohistochemical staining revealed that OPN, matrix metalloproteinase (MMP)9 and hypoxia-inducible factor (HIF)-1alpha have statistically significant different expression patterns between well- and poorly differentiated tissue samples (P < 0.05). Correlations existed between OPN and MMP9, and between OPN and HIF-1 (r(1) = 0.872, p(1) < 0.01 and r(2) = 0.878, p(2) < 0.01). Furthermore, OPN dramatically increased colony formation and invasion of gastric cancer cells in vitro and promoted tumour growth and metastasis in vivo. In addition, OPN potently protected gastric cancer cells from serum depletion-induced apoptosis. Further study shows that OPN activated phosphoinositide 3-kinase/Akt survival pathway and up-regulated HIF-1alpha via binding to v3 integrins in gastric cancer cells. Moreover, we found that OPN could activate MMP9 and upregulate MMP2. Taken together, our results suggest that the survival-promoting function is crucial for OPN to promote the development of gastric cancer, and HIF-1 and MMP9 may play key roles during this process. Thus, targeting OPN and its related signalling network may develop an effective therapeutic approach for the management of gastric cancer.