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

• Project/Area Number: 15590620
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: TERATANI Takuma The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (30359616)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Haruhiko The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (60240305) ; KATO Naoya The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (90313220) ; KAWAKAMI Takayuki The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員 (60376457) ; OTSUKA Motoyuki The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: vitaminK / hepatocellular carcinoma / DCP

Research Abstract

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.

Research Products

• [Journal Article] Proposal of a new prognostic model for hepatocellular carcinoma : an analysis of 403 patients. (2005)
  • Author(s): Tateishi R, Yoshida H, Shiina S, Imamura H, Hasegawa K, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Makuuchi M, Omata M.
  • Journal Title: Gut 54(3) Pages: 419-425
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways. (2005)
  • Author(s): Shao RX, Otsuka M, Kato N, Taniguchi H, Hoshida Y, Moriyama M, Kawabe T, Omata M.
  • Journal Title: Gastroenterology 128(1) Pages: 86-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Proposal of a new prognostic model for hepatocellular carcinoma : an analysis of 403 patients. (2005)
  • Author(s): Tateishi R, Yoshida H, Shiina S, Imamura H, hasegawa K, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Makuuchi M, Omata M.
  • Journal Title: Gut 54(3) Pages: 419-425
• [Journal Article] Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. (2004)
  • Author(s): Otsuka M, Kato N, Shao RX, Hoshida Y, Ijichi H, Koike Y, Taniguchi H, Moriyama M, Shiratori Y, Kawabe T, Omata M.
  • Journal Title: Hepatology 40(1) Pages: 243-251
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vitamin K2 inhibits the growth and invasiveness of hepatocellular Carcinoma cells via protein kinase A activation. (2004)
  • Author(s): Otsuka M, Kato N, Shao RX, Hoshida Y, Ijichi H, Koike Y, Taniguchi H, Moriyama M, Shiratori Y, Kawabe T, Omata M.
  • Journal Title: Hepatology 40(1) Pages: 243-251
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Factors affecting the prognosis of patients with hepatocellular carcinoma invading the portal vein--a retrospective analysis using 952 consecutive HCC patients (2003)
  • Author(s): Koike Y, Nakagawa K, Shiratori Y, Shiina S, Imamura M, Sato S, Obi S, Teratani T, Hamamura K, Yoshida H, Omata M.
  • Journal Title: Hepatogastroenterology 50(54) Pages: 2035-2039
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Percutaneous radiofrequency ablation for hepatocellular carcinoma.
  • Author(s): Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Yoshida H, Kawabe T, Omata M.
  • Journal Title: Cancer (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vitamin K2 binds 17b-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism
  • Author(s): Otsuka M, Kato N, Ichimura T, Abe S, Tanaka Y, Taniguchi H, Hoshida Y, Moriyama M, Wang Y, Shao R-X, Narayan D, Muroyama R, Kanai F, Kawabe T, Isobe T, Omata M.
  • Journal Title: Life Sciences (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Percutaneous radiofrequency ablation for hepatocellular carcinoma
  • Author(s): Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Yoshida H, Kawabe T, Omata M.
  • Journal Title: Cancer (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vitamin K2 binds 17b-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism
  • Author(s): Otsuka M, Kato N, Ichimura T, Abe S, Tanaka Y, Taniguchi H, Hoshida Y, Moriyama M, Wang Y, Shao R-X, Narayan D, Muroyama R, Kanai F, Kawabe T, Isobe T, Omata M.
  • Journal Title: Life Sciences (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Percutaneous radiofrequency ablation for hepatocellular carcinoma.
  • Author(s): Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Yoshida H, Kawabe T, Omata M.
  • Journal Title: Cancer (印刷中)
• [Journal Article] Vitamin K2 binds 17b-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism
  • Author(s): Otsuka M, Kato N, Ichimaru T, Abe S, Tanaka Y, Taniguchi H, Hoshida Y, Moriyama M, Wang Y, Shao R-X, Narayan D, Muroyama R, Kanai F, Kawabe T, Isobe T, Omata M.
  • Journal Title: Life Sciences (印刷中)
• [Publications] Yoshida H, Tateishi R, Arakawa Y, Sata M, Fujiyama S, Nishiguchi S, Ishibashi H, Yamada G, Yokosuka O, Shiratori Y, Omata M: "Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C."Gut. 53(3). 425-430 (2004)
• [Publications] Koike Y, Nakagawa K, Shiratori Y, Shiina S, Imamura M, Sato S, Obi S, Teratani T, Hamamura K, Yoshida H, Omata M: "Factors affecting the prognosis of patients with hepatocellular carcinoma invading the portal vein--a retrospective analysis using 952 consecutive HCC Patients."Hepatogastroenterology. 50(54). 2035-2039 (2003)
• [Publications] Taniguchi H, Kato N, Otsuka M, Goto Y, Yoshida H, Shiratori Y, Omata M: "Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription."J Med Virol. 72(1). 52-59 (2004)
• [Publications] Otsuka M, Arai M, Mori M, Kato M, Kato N, Yokosuka O, Ochiai T, Takiguchi M, Omata M, Seki N: "Comparing gene expression profiles in human liver, gastric, and Pancreatic tissues using full-length-enriched cDNA Libraries."Hepatol Res. 27(1). 76-82 (2003)
• [Publications] Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Koike Y, Yoshida H, Omata M: "Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus."Ann Intern Med. 138(4). 299-306 (2003)
• [Publications] 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)