论文摘要
Osteopontin(OPN)是最早从骨基质中分离得到的一种分泌型、粘附性的钙结合磷酸化糖蛋白。OPN通过与其主要的受体整合素和CD44相互作用,参与多组织、多器官的生理病理过程。近年发现OPN还是一种与肿瘤发生发展密切相关的多功能细胞外基质蛋白。OPN在乳腺癌、前列腺癌、肝癌、结肠癌、食管癌、肺癌和神经胶质瘤等许多肿瘤组织中高表达,并提示OPN与肿瘤细胞存活、侵袭转移和血管生成密切相关。胃癌是中国最常见的发病率和死亡率很高的恶性肿瘤之一。胃癌的发生发展涉及到多基因的改变,包含抑癌基因失活,癌基因的扩增及肿瘤转移相关基因的异常表达等。前人研究发现OPN mRNA在胃癌组织中的表达较正常胃粘膜组织高。然而,OPN在胃癌发生发展中的功能及其作用机制并不清楚。我们首先利用免疫组织化学染色的方法在非胃癌组织和胃癌组织中检测了OPN、MMP9、HIF-1α和CD34的表达和分布。结果显示,在非胃癌组织中均未能检测到OPN、MMP9和HIF-1α的表达。胃癌组织中MVD显著高于正常胃粘膜组织,而且发现OPN、MMP9或HIF-1α表达量高的胃癌组织中,MVD值就越高。统计学方法分析,OPN、MMP9、HIF-1α和MVD在有、无淋巴结转移的胃癌组织中或在高、低分化腺瘤中的阳性表达率均呈显著性差异(p<0.05)。相关性分析表明OPN与MMP9和HIF-1α的表达分别具有相关性(r=0.872,p<0.01和r=0.878,p<0.01),提示OPN、MMP9和HIF-1α在胃癌的发生发展进程中的作用是相互关联的。为进一步探讨OPN在胃癌细胞存活与侵袭、转移中的作用机制,我们构建了稳定表达OPN的人胃癌OPN/SGC7901细胞株和转染空载体的Vec/SGC7901细胞株,并以此为研究模型。研究发现,在无血清和姜黄素诱导生存压力条件下,OPN均可通过激活PI3-K/Akt信号通路来拮抗细胞凋亡,促进胃癌SGC7901细胞存活,通过外源重组的OPN蛋白刺激,我们也得到了同样的结果。进一步用αvβ3抗体阻断OPN与其结合,发现Akt磷酸化水平降低,说明在压力条件下,OPN可通过与整合素αvβ3结合激活PI3-K/Akt信号通路,从而促进胃癌细胞SGC7901的存活。
论文目录
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