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

  • Authors:
    • Kazumoto Murata
    • Atsushi Sakamoto
  • View Affiliations

  • Published online on: December 1, 2008     https://doi.org/10.3892/ijo_00000104
  • Pages: 1149-1155
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

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 naïve 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.

Related Articles

Journal Cover

December 2008
Volume 33 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Murata K and Murata K: 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. Int J Oncol 33: 1149-1155, 2008
APA
Murata, K., & Murata, K. (2008). 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. International Journal of Oncology, 33, 1149-1155. https://doi.org/10.3892/ijo_00000104
MLA
Murata, K., Sakamoto, A."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". International Journal of Oncology 33.6 (2008): 1149-1155.
Chicago
Murata, K., Sakamoto, A."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". International Journal of Oncology 33, no. 6 (2008): 1149-1155. https://doi.org/10.3892/ijo_00000104