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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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          Author and article information

          Journal
          Clin. Exp. Med.
          Clinical and experimental medicine
          Springer Science and Business Media LLC
          1591-9528
          1591-8890
          Feb 2019
          : 19
          : 1
          Affiliations
          [1 ] Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, 116000, Liaoning, People's Republic of China.
          [2 ] Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, People's Republic of China.
          [3 ] Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China.
          [4 ] Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, 116000, Liaoning, People's Republic of China. wangjingyus@163.com.
          [5 ] Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, 116000, Liaoning, People's Republic of China. 1062880793@qq.com.
          Article
          10.1007/s10238-018-0528-z
          10.1007/s10238-018-0528-z
          30306378

          Coagulopathy, ERK, Hepatocellular carcinoma, VKORC1, mTOR

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