Mechanism of PIVKA-II production in hepatocellular carcinoma

缺乏维生素K或拮抗剂II诱导的蛋白（PIVKA-II）是一种公认的肝细胞癌（HCC）肿瘤标志物，但其产生的确切机制尚不清楚。我们最近证明，在上皮间质转化（EMT）的表型变化过程中，细胞骨架重排通过损害维生素K的摄取，在PIVKA-II的产生中起着至关重要的作用。此外，我们证明了缺氧刺激以同样的方式诱导HCC细胞产生PIVKA-II。我们还证明，缺氧和营养不良导致的进一步表型变化会通过mTOR途径减弱HCC细胞中蛋白质的合成，导致PIVKA-II的产生减少。因此，我们的一系列研究结果表明，PIVKA-II可能是HCC的表型标志物，也可能是肿瘤标志物。

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an established tumor marker for hepatocellular carcinoma (HCC), but precise mechanism of its production is unknown. We recently demonstrated that cytoskeletal rearrangement during phenotypic changes involved in epithelial mesenchymal transition (EMT) plays a crucial role in PIVKA-II production through impairment of vitamin K uptake. In addition, we demonstrated that hypoxic stimulation induced HCC cells to produce PIVKA-II in the same way. We also demonstrated that further phenotypic changes by hypoxia with malnutrition attenuated protein synthesis in HCC cells through mTOR pathway, resulting in decrease of PIVKA-II production. Thus, our serial findings indicate that PIVKA-II could be a phenotypic marker of HCC as well as a tumor marker.