Analyses of molecular mechanisms of hepatocellular carcinoma cell growth suppression induced by vitamin K

维生素K抑制肝癌细胞生长的分子机制分析

• 批准号: 15590620
• 负责人: TERATANI Takuma
• 金额: $ 2.24万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590620/
• 关键词: vitaminK; hepatocellular carcinoma; DCP

Hepatocellular carcinoma (HCC) is a common human malignancy. Its high mortality rate is mainly a result of high intrahepatic recurrence and portal venous invasion. We previously reported that the development of portal venous invasion is related to levels of des-gamma-carboxy prothrombin (DCP), a serum protein that increases at a notably higher rate in patients with HCC. Because DCP is produced by a vitamin K shortage, we examined the biological effects of extrinsic supplementation of vitamin K2 in HCC cells in vitro. Consequently, vitamin K2 inhibits the growth and invasion of HCC cells through the activation of protein kinase A (PKA), which modulates the activities of several transcriptional factors, independent of suppression of DCP. In addition, vitamin K-binding proteins were characterized by pull-down experiment using a chemically synthesized biotynylated vitamin K followed by mass spectrometric identification of the pull-downed components. The results showed that Vitamin K2 binds 17β hydroxysteroid dehydrogenase 4 and decreases the intracellular estradiol : estrone ratio. These results suggest a possible role for vitamin K in modulating cell growth and estrogen function, and vitamin K2 may be a promising drug for hepatocellular carcinoma.

肝细胞癌是一种常见的人类恶性肿瘤。其高病死率主要是肝内复发和门静脉侵犯所致。我们先前报道，门静脉侵犯的发生与DES-伽玛-羧基凝血酶原(DCP)水平有关，DCP是一种血清蛋白，在肝细胞癌患者中以显著更高的速度增加。由于DCP是由维生素K缺乏产生的，我们在体外检测了外源性补充维生素K2对肝癌细胞的生物学效应。因此，维生素K2通过激活蛋白激酶A(PKA)来抑制肝癌细胞的生长和侵袭，PKA调节几种转录因子的活性，而不依赖于对DCP的抑制。此外，使用化学合成的生物苷化维生素K进行下拉实验，然后对下拉组分进行质谱分析，对维生素K结合蛋白进行了表征。结果表明，维生素K2能与17β羟基类固醇脱氢酶4结合，降低细胞内雌二醇/雌酮的比值。这些结果提示维生素K可能在调节细胞生长和雌激素功能中起作用，维生素K2可能是治疗肝细胞癌的一种有前途的药物。

项目成果

Moriyama M, Hoshida Y, Otsuka M, Nishimura S, Kato N, Goto T, Taniguchi H, Shiratori Y, Seki N, Omata M: "Relevance network between chemosensitivity and transcriptome in human hepatomacells."Mol Cancer Ther. 2(2). 199-205 (2003)

Moriyama M、Hoshida Y、Otsuka M、Nishimura S、Kato N、Goto T、Taniguchi H、Shiratori Y、Seki N、Omata M：“人类肝细胞中化学敏感性和转录组之间的相关网络。”Mol Cancer Ther。

Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways

• DOI: 10.1053/j.gastro.2004.09.077
• 发表时间: 2005-01-01
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Shao, RX;Otsuka, M;Omata, M
• 通讯作者: Omata, M

Factors affecting the prognosis of patients with hepatocellular carcinoma invading the portal vein - a retrospective analysis using 952 consecutive HCC patients.

影响侵犯门静脉的肝细胞癌患者预后的因素——对 952 例连续 HCC 患者的回顾性分析。

• 发表时间: 2003
• 期刊: Hepatogastroenterology 50
• 作者: Koike;Y.
• 通讯作者: Y.

Percutaneous radiofrequency ablation for hepatocellular carcinoma.

经皮射频消融术治疗肝细胞癌。

• 期刊: Cancer (印刷中)
• 作者: Tateishi R;Shiina S;Teratani T;Obi S;Sato S;Koike Y;Fujishima T;Yoshida H;Kawabe T;Omata M.
• 通讯作者: Omata M.

Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients

• DOI: 10.1136/gut.2003.035055
• 发表时间: 2005-03-01
• 期刊: GUT
• 影响因子: 24.5
• 作者: Tateishi, R;Yoshida, H;Omata, M
• 通讯作者: Omata, M