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mTOR and ERK regulate VKORC1 expression in both hepatoma cells and hepatocytes which influence blood coagulation

  • Yaofu Liu
  • Huiling Li
  • Jianyi Dong
  • Lei Ma
  • Aijun Liao
  • Zhuona Rong
  • Zhi Zhou
  • Liang Cao
  • Fujin Wang
  • Jingyu Wang
  • Aiguo Wang
Original Article

Abstract

Deficiency of γ-glutamyl carboxylation of coagulation factors, as evidenced by the elevated level of Des-γ-carboxyl prothrombin (DCP), is a common feature in hepatocellular carcinoma patients. Additionally, treatment of cancer patients with mTOR inhibitors significantly increases hemorrhagic events. However, the underlying mechanisms remain unknown. In the present study, Vitamin K epoxide reductase complex subunit 1 (VKORC1) was found to be significantly down-regulated in clinical hepatoma tissues and most tested hepatoma cell lines. In vitro investigations showed that VKORC1 expression was promoted by p-mTOR at the translational level and repressed by p-ERK at the transcriptional level. By exploring Hras12V transgenic mice, a hepatic tumor model, VKROC1 was significantly down-regulated in hepatic tumors and showed prolonged activated partial prothrombin time (APTT). In vivo investigations further showed that VKORC1 expression was promoted by p-mTOR and repressed by p-ERK in both hepatoma and hepatocytes. Consistently, APTT and prothrombin time were significantly prolonged under the mTOR inhibitor treatment and significantly shortened under the ERK inhibitor treatment. Conclusively, these findings indicate that mTOR and ERK play crucial roles in controlling VKORC1 expression in both hepatoma and hepatocytes, which provides a valuable molecular basis for preventing hemorrhage in clinical therapies.

Keywords

Hepatocellular carcinoma Coagulopathy VKORC1 mTOR ERK 

Abbreviations

APTT

Activated partial prothrombin time

DCP

Des-γ-carboxyl prothrombin

ERK

Extracellular signal-regulated kinase

GGCX

Gamma-glutamyl carboxylase

HCC

Hepatocellular carcinoma

mTOR

Mammalian target of rapamycin

NGS

Next-generation sequencing

P

Hepatic tumor-adjacent normal liver tissues

PT

Prothrombin time

Ras-Tg mice

Hras12V transgenic mice

T

Hepatic tumor tissues

TF

Tissue factor

VK

Vitamin K

VKDB

Vitamin K deficiency-related bleeding

VKORC1

Vitamin K epoxide reductase complex subunit 1

Wt

Wild-type mice or normal liver tissues of wild-type mice

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (30872950). A. G. Wang and J. Y. Wang conceived of the research ideas, supervised the project and revised the manuscript. Y. F. Liu and H. L. Li performed experiments, analyzed data and wrote the manuscript. J. Y. Dong, L. Ma, A. J. Liao, Z. N. Rong, L. Cao, Z, Zhou. F. J. Wang conducted animal and molecular experiments. L. Ma, A. J. Liao recruited clinical data and human samples in the clinical study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Yaofu Liu
    • 1
    • 2
  • Huiling Li
    • 1
  • Jianyi Dong
    • 1
  • Lei Ma
    • 1
  • Aijun Liao
    • 1
  • Zhuona Rong
    • 1
  • Zhi Zhou
    • 1
  • Liang Cao
    • 3
  • Fujin Wang
    • 1
  • Jingyu Wang
    • 1
  • Aiguo Wang
    • 1
  1. 1.Department of Comparative Medicine, Laboratory Animal CenterDalian Medical UniversityDalianPeople’s Republic of China
  2. 2.Suzhou Institute of Systems Medicine, Center for Systems MedicineChinese Academy of Medical SciencesSuzhouPeople’s Republic of China
  3. 3.Department of General Surgery, The First Affiliated HospitalDalian Medical UniversityDalianPeople’s Republic of China

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