Osteopontin splice variants differentially modulate the migratory activity of hepatocellular carcinoma cell lines
Osteopontin splice variants differentially modulate the migratory activity of hepatocellular carcinoma cell lines
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DOI：
10.3892/ijo_00000458
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发表时间：
2009-12-01
影响因子：
5.2
通讯作者：
Kim, Kyu-Won
中科院分区：
文献类型：
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作者：
Chae, Sujin;Jun, Hyoung-Oh;Kim, Kyu-Won
骨桥蛋白（OPN, SPP1）是一种分泌性细胞外基质蛋白，与癌症相关机制如转移、侵袭和血管生成有关。已知存在三种OPN异构体（OPN-a， -b和-c），它们来源于选择性剪接，但其功能特异性尚不清楚。在这里，我们发现OPN亚型在肝细胞癌（HCC）细胞系和患者组织中的表达谱与HCC的特定细胞表型和致瘤性相关。因此，具有强大迁移能力的SK-Hep1细胞主要表达OPN-a和-b，而Hep3B和PLC/PRF/5等非迁移细胞系主要表达OPN-c。肿瘤组织主要表达OPN-a和-b，而正常肝组织主要表达OPN-c。Transwell浸润和伤口诱导迁移实验显示，OPN-a和-b均能诱导Hcp3B细胞迁移，而OPN-c无显著影响。相比之下，OPN-c抑制了SK-Hep1细胞的迁移活性，但OPN-a对SK-Hep1细胞的迁移活性无明显影响。一致地，OPN异构体形成了差异激活的迁移相关信号通路，例如OPN-a和-b增加了尿激酶型纤溶酶原激活剂的表达和p42/p44 MAP激酶的磷酸化，但这些通路不被OPN-c激活。因此，本研究的结果表明，OPN剪接变异与信号通路的差异偶联调节了HCC细胞的迁移特性，这是HCC进展病理异质性的机制之一。
Osteopontin (OPN, SPP1) is a secretory extracellular matrix protein that has been implicated in cancer-associated mechanisms such as metastasis, invasion and angiogenesis. Three OPN isoforms (OPN-a, -b and -c) derived from alternative splicing are known to exist, but their functional specificity remains unclear. Here, we found that the expression profile of OPN isoforms in hepatocellular carcinoma (HCC) cell lines and patient tissues were correlated with specific cellular phenotypes and tumorigenicity of HCC. Thus, SK-Hep1 cells with a robust migratory capacity dominantly expressed both OPN-a and -b, but non-migratory cell lines such as Hep3B and PLC/PRF/5 mainly expressed OPN-c. Moreover, tumor tissues predominantly expressed OPN-a and -b, whereas normal liver tissues mainly expressed OPN-c. Transwell infiltration and wound-induced migration assays revealed that both OPN-a and -b induced Hcp3B cell migration, while OPN-c had no significant effects. By contrast, OPN-c suppressed the migratory activity of SK-Hep1 cells although no significant changes were induced by OPN-a. Consistently, OPN isoforms differentially activated migration-associated signaling pathways such that OPN-a and -b increased the expression of urokinase type plasminogen activator and the phosphorylation of p42/p44 MAP kinase, but these pathways were not activated by OPN-c. Thus, the findings of the present study Suggest that OPN splice variants differentially couple to signaling pathways to modulate the migratory property of HCC cells and that this is one of the mechanisms underlying the pathological heterogeneity of HCC progression.