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

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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.

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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

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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.

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  1. Yaofu Liu and Huiling Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, 116000, Liaoning, People’s Republic of China

    Yaofu Liu, Huiling Li, Jianyi Dong, Lei Ma, Aijun Liao, Zhuona Rong, Zhi Zhou, Fujin Wang, Jingyu Wang & Aiguo Wang

  2. Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, People’s Republic of China

    Yaofu Liu

  3. Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, People’s Republic of China

    Liang Cao

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  1. Yaofu Liu
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Liu, Y., Li, H., Dong, J. et al. mTOR and ERK regulate VKORC1 expression in both hepatoma cells and hepatocytes which influence blood coagulation. Clin Exp Med 19, 121–132 (2019). https://doi.org/10.1007/s10238-018-0528-z

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