Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, 116000, Liaoning, People's Republic of China.
Suzhou Institute of Systems Medicine, Center for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, People's Republic of China.
Clin Exp Med. 2019 Feb;19(1):121-132. doi: 10.1007/s10238-018-0528-z. Epub 2018 Oct 10.
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.
γ-谷氨酰羧化凝血因子缺乏，表现为去γ-羧基凝血酶原（DCP）水平升高，是肝细胞癌患者的常见特征。此外，mTOR 抑制剂治疗癌症患者会显著增加出血事件。然而，其潜在机制尚不清楚。本研究发现，维生素 K 环氧化物还原酶复合物亚基 1（VKORC1）在临床肝癌组织和大多数测试的肝癌细胞系中均显著下调。体外研究表明，p-mTOR 在翻译水平上促进 VKORC1 的表达，而 p-ERK 在转录水平上抑制其表达。通过探索 Hras12V 转基因小鼠这一肝肿瘤模型，发现 VKROC1 在肝肿瘤中显著下调，并表现出延长的活化部分凝血活酶时间（APTT）。体内研究进一步表明，在肝癌和肝细胞中，p-mTOR 促进 VKORC1 的表达，而 p-ERK 则抑制其表达。一致地，mTOR 抑制剂治疗可显著延长 APTT 和凝血酶原时间，而 ERK 抑制剂治疗则显著缩短其时间。综上，这些发现表明，mTOR 和 ERK 在控制肝癌和肝细胞中 VKORC1 的表达中起关键作用，为临床治疗中预防出血提供了有价值的分子基础。
