Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1α up-regulation and MMP9 activation
Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1α up-regulation and MMP9 activation
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DOI：
10.1111/j.1582-4934.2008.00540.x
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发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Hu, Tianhui
中科院分区：
文献类型：
--
作者：
Song, Gang;Ouyang, Gaoliang;Hu, Tianhui
骨桥蛋白（OPN）是一种分泌型的整合素结合基质磷酸化糖蛋白。OPN已被证明促进恶性肿瘤的进展和转移，并在包括胃癌在内的几种类型的癌症中具有预后价值。然而，OPN介导胃癌转移生长的作用机制尚不清楚。在这里，我们使用多种体外和体内模型，报告OPN强烈促进胃癌的进展和转移。免疫组化显示OPN、基质金属蛋白酶（MMP）9和缺氧诱导因子（HIF）-1 α在高分化和低分化组织中的表达差异有统计学意义（P < 0.05）。OPN与MMP 9、HIF-1 α之间存在相关性（r（1）= 0.872，p（1）< 0.01; r（2）= 0.878，p（2）< 0.01）。此外，OPN在体外显著增加胃癌细胞的集落形成和侵袭，在体内促进肿瘤的生长和转移。此外，OPN还能有效地保护胃癌细胞免受血清耗竭诱导的凋亡。进一步的研究表明，OPN通过与α（v）β（3）整合素结合，激活磷酸肌醇3激酶/Akt生存通路，上调HIF-1 α表达。此外，我们发现OPN可以激活MMP 9并上调MMP 2。综上所述，我们的研究结果表明，OPN促进胃癌发生发展的生存功能是至关重要的，HIF-1 α和MMP 9可能在此过程中发挥关键作用。因此，靶向OPN及其相关信号网络可能会为胃癌的管理开发一种有效的治疗方法。
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)-1 alpha 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 alpha (r(1) = 0.872, p(1) < 0.01 and r(2) = 0.878, p2 < 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-1 alpha via binding to alpha(v)beta(3) integrins in gastric cancer cells. Moreover, we found that OPN could activate MMP9 and up-regulate 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 alpha 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.