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Impairment of clathrin-mediated endocytosis via cytoskeletal change by epithelial to fibroblastoid conversion in HepG2 cells: A possible mechanism of des-γ-carboxy prothrombin production in hepatocellular carcinoma

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Des-γ-carboxy prothrombin (DCP) has been well established as a hepatocellular carcinoma (HCC) tumor marker. However, the precise mechanism by which HCC cells produce DCP remains unknown. Importantly, DCP is not specific for HCC. For example, vitamin K-deficiency or ingestion of a vitamin K antagonist (warfarin) also leads to DCP production. In addition, supplementary administration of vitamin K2 analogues to HCC patients has led to reduce serum DCP levels. From these observations, we hypothesize that DCP might be produced from HCC cells with functional impairment of vitamin K uptake. Because, as previously reported, the down-regulation of E-cadherin or high serum DCP in HCC patients is associated with a high risk of vascular invasion, intra-hepatic metastasis and tumor recurrence, we examined if HCC cells might produce DCP by epithelial to fibroblastoid conversion (EFC) in vitro. HepG2 cells were induced EFC by tumor promoter, 12-O-tetracanoylphorbol-13-acetate (TPA). DCP production was observed in HepG2 cells that had lost E-cadherin expression in a TPA-dose-dependent manner. The DCP production was inhibited by introducing additional vitamin K2 into the treated cells. In addition, LDL uptake as a surrogate of vitamin K uptake was significantly impaired in TPA-treated HepG2 cells. The cells with impairment of LDL uptake produced DCP. Fat soluble vitamins are taken up into cells through clathrin-mediated endocytosis, in which the dynamic polymerization of F-actin plays a crucial role. We found that HepG2 cells with F-actin rearrangement produced DCP. In addition, latrunculin A, an actin depolymerizer, induced na├»ve HepG2 cells to produce DCP, confirming that impairment of F-actin polymerization is a key mechanism of DCP production. We showed in vitro that cytoskeletal filament change by EFC is crucial for DCP production in HepG2 cells.
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Document Type: Research Article

Affiliations: Center for Community Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan., Email: [email protected]

Publication date: January 1, 2008

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  • The International Journal of Oncology provides an international forum for the publication of the latest, cutting-edge research in the broad area of oncology and cancer treatment. The journal accepts original high quality works and reviews on all aspects of oncology research including carcinogenesis, metastasis, epidemiology, chemotherapy and viral oncology. Through fair and efficient peer review, the journal is dedicated to publishing top tier research in the field, offering authors rapid publication as well as high standards of copy-editing and production. The International Journal of Oncology is published on a monthly basis in both print and early online.
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