Hypoxia-induced des-γ-carboxy prothrombin production in hepatocellular carcinoma
Hypoxia-induced des-γ-carboxy prothrombin production in hepatocellular carcinoma
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DOI：
10.3892/ijo_00000487
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发表时间：
2010-01-01
影响因子：
5.2
通讯作者：
Sakamoto, Atsushi
中科院分区：
文献类型：
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作者：
Murata, Kazumoto;Suzuki, Hideto;Sakamoto, Atsushi
脱伽马羧基凝血酶原 (DCP) 是一种已确定的 HCC 肿瘤标志物，但其产生的确切机制仍不清楚。最近，我们证明化学物质诱导的上皮细胞向成纤维细胞转化 (EFC) 或上皮间质转化 (EMT) 过程中的细胞骨架变化通过维生素 K 摄取受损在 DCP 产生中发挥着关键的机制作用。我们提出的 DCP 产生机制与大量临床证据一致。补充维生素 K2 类似物可降低肝细胞癌 (HCC) 患者的血清 DCP 水平。 HCC患者血清DCP高与血管侵犯、转移和肿瘤复发有关。另一方面，据报道缺氧会诱导 EMT 或细胞骨架变化。因此，我们研究了缺氧是否会在 HCC 细胞的 EFC 或 EMT 过程中诱导 DCP 产生。事实上，低氧刺激诱导肝癌细胞系（HepG2 或 PLC/PRF/5 细胞）经历 EFC 或 EMT，并且这些细胞产生 DCP。免疫荧光研究表明，缺氧刺激会损害标记的低密度脂蛋白的摄取，而标记的低密度脂蛋白是维生素 K 摄取的替代品。此外，在 DCP 产生细胞中，细丝状肌动蛋白网络在缺氧刺激下被破坏，该网络对于网格蛋白介导的维生素 K 内吞作用至关重要。因此，低氧刺激诱导 HCC 细胞以与化学物质相同的机制产生 DCP。此外，使用手术切除的 HCC 样本进行的免疫组织化学研究表明，在 DCP 染色强度较强的 HCC 细胞中更常见到核缺氧诱导因子 (HIF)-1 α 的阳性染色。重要的是，临床观察表明 DCP 作为 HCC 肿瘤标志物在较大的肿瘤中更有用，这些肿瘤在肿瘤发展过程中可能会暴露于缺氧，这支持了我们的结果。
Des-gamma-carboxy prothrombin (DCP) is an established HCC tumor marker, but the precise mechanism of its production is still unclear. Recently, we demonstrated that cytoskeletal changes during epithelial-to-fibroblastoid conversion (EFC) or epithelial mesenchymal transition (EMT) induced by chemicals plays a critical mechanistic role in DCP production via impairment in vitamin K uptake. Our proposed mechanism of DCP production is consistent with Substantial clinical evidence. Supplementary vitamin K2 analogues reduced serum DCP levels in hepatocellular carcinoma (HCC) patients. HCC patients with high serum DCP are associated with vascular invasion, metastasis and tumor recurrence. On the other hand, hypoxia has been reported to induce EMT or cytoskeletal changes. Therefore, we examined whether hypoxia induced DCP production during EFC or EMT in HCC cells. Indeed, hypoxic stimulation induced hepatoma cell lines (HepG2 or PLC/PRF/5 cells) to undergo EFC or EMT and these cells produced DCP. Immunofluorescence study demonstrated that hypoxic stimulation impaired labeled low-density lipoprotein uptake, which was a surrogate for vitamin K uptake. In addition, fine filamentous actin network, which has crucial role for clathrin-mediated endocytosis of vitamin K, was disrupted in DCP producing cells by hypoxic stimulation. Thus, hypoxic stimulation induced HCC cells to produce DCP in the same mechanism as chemicals. Furthermore, immunohistochemical study using surgically resected HCC samples showed that a positive staining of nuclear hypoxia inducible factor (HIF)-1 alpha was more frequently observed in HCC cells with stronger staining intensity of DCP. Importantly, clinical observations that DCP as an HCC tumor marker was more useful in larger tumors, which is likely to be exposed with hypoxia during tumor development, support our results.