Liver regeneration was affected by carboxylase gene transfer.

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 16390210
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Okayama University
• Principal Investigator: SHIRAHA Hidenori University Hospital of Medical and Dentistry, Department of Gastroenterology and Hepatology, Research Associate, 医学部・歯学部附属病院, 助手 (40379748)
• Co-Investigator(Kenkyū-buntansha): SAKAGUCHI Kohsaku Graduate School of Medicine, Dentistry and Pharmaceutical Science Medicine, Department of Medicine and Medical Science, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (90235143) ; TAKAKI Akinobu University Hospital of Medical and Dentistry, Department of Gastroenterology and Hepatology, Research Associate, 医学部・歯学部附属病院, 助手 (80359885) ; KATO Jun University Hospital of Medical and Dentistry, Department of Gastroenterology and Hepatology, Research Associate, 医学部・歯学部附属病院, 助手 (90379743)
• Project Period (FY): 2004 – 2006
• Keywords: liver regeneration / angiogenesis / tumor marker

Research Abstract

In the current study, we investigate the effect of gene transfer in liver regeneration. Gamma-glutamyl carboxylase (GGCX) is known as a rate-limiting enzyme in the conversion of des-gamma-carboxy prothrombin (DCP) into normal prothrombin. DCP stimulated cell proliferative activities 1.5-2.0 fold in Hep3B and SK-Hep-1 cells. This effect was brought through activation of Met-JAK1-STAT3 signaling pathway. Moreover, DCP stimulated human umbilical vein endothelial cells (HUVEC). The cell migrative activity and cell proliferative activity were enhanced 2.2 fold and 1.5 fold, respectively by DCP in HUVEC. This effect was caused by activation of phospholipase-C-γ and erk-MAPK. Variant type of GGCX was cloned from hepatocellular carcinoma cell line by RT-PCR. Introduction of variant type-GGCX cDNA converted DCP-negative cell lines into DCP-producing cells. Introduction of siRNA against GGCX showed same effect as introduction of variant type-GGCX. These cells showed enhanced cell migration and proliferation. In conclusion, introduction of variant type-GGCX and siRNA against GGCX might be an effective strategy to control cell proliferation of hepatocyte and angiogenesis in liver regeneration.

Research Products

• [Journal Article] A homosexual Japanese man with acute hepatitis due to hepatitis B virus genotype ae, concurrent with amebic colitis. (2007)
  • Author(s): Miyake Y, Iwasaki Y, Ishikawa S, Tatsukawa M, Nawa T, Kato J, Takaki A, Kobashi H, Sakaguchi K, Shiratori Y
  • Journal Title: Acta Med Okayama. 61・1 Pages: 35-39
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Des-gamma -carboxy prothrombin-promoted vascular endothelial cell proliferation and migration. (2007)
  • Author(s): Fujikawa T, Shiraha H, Ueda N, Takaoka N, Nakanishi Y, Matsuo N, Tanaka S, Nishina SI, Suzuki M, Takaki A, Sakaguchi K, Shiratori Y
  • Journal Title: J Biol Chem. 282・12 Pages: 8741-8748
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cimetidine inhibits epidermal growth factor-induced cell signaling (2007)
  • Author(s): Fujikawa T, Shiraha H, Shiratori Y, et al.
  • Journal Title: Journal of Gastroenterology and Hepatology 22・3 Pages: 436-443
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Short-term high-dose followed by long-term low-dose hepatitis B immunoglobulin and lamivudine therapy prevented recurrent hepatitis B after liver transplantation. (2007)
  • Author(s): Takaki A, Yagi T, Iwasaki Y, Sadamori H, Matsukawa H, Matsuda H, Shinoura S, Umeda Y, Miyake Y, Terada R, Kobashi H, Sakaguchi K, Tanaka N, Shiratori Y
  • Journal Title: Transplantation. 83・2 Pages: 231-233
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical characteristics of synchronous colorectal cancer are different according to tumour location. (2007)
  • Author(s): Fukatsu H, Kato J, Nasu JI, Kawamoto H, Okada H, Yamamoto H, Sakaguchi K, Shiratori Y
  • Journal Title: Dig Liver Dis. 39・1 Pages: 40-46
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contrast-enhanced ultrasonography depicts small tumor vessels for the evaluation of pancreatic tumors. (2007)
  • Author(s): Okamoto Y., Kawamoto H., Takaki A., Ishida E., Ogawa T., Kuwaki K., Kobayashi Y., Sakaguchi K., Shiratori Y.
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  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A homosexual Japanese man with acute hepatitis due to hepatitis B virus genotype ae, concurrent with amebic colitis. (2007)
  • Author(s): hepatitis C virus infection may improve patient survival.Miyake, Y., Iwasaki, Y., Ishikawa, S., Tatsukawa, M., Nawa, T., Kato, J., Takaki, A., Kobashi, H., Sakaguchi, K., Shiratori, Y.
  • Journal Title: Acta Med Okayama. 61 Pages: 35-39
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cimetidine inhibits epidermal growth factor-induced cell signaling. (2007)
  • Author(s): Fujikawa T., Shiraha H., Nakanishi Y., Takaoka N., Ueda N., Suzuki M.Shiratori Y.
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 436-443
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migration. (2007)
  • Author(s): Fujikawa T., Shiraha H., Ueda N., Takaoka N., Nakanishi Y., Matsuo N., Tanaka S., Nishina S., Suzuki M., Takaki A., Sakaguchi K.Shiratori Y.
  • Journal Title: J Biol Chem 282 Pages: 8741-8748
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Short-term high-dose followed by long-term low-dose hepatitis B immunoglobulin and lamivudine therapy prevented recurrent hepatitis B after liver transplantation. (2007)
  • Author(s): Takaki A., Yagi T., Iwasaki Y., Sadamori H., Matsukawa H., Matsuda H., Shinoura S., Umeda Y., Miyake Y., Terada R., Kobashi H., Sakaguchi K., Tanaka N., Shiratori Y.
  • Journal Title: Transplantation. 83 Pages: 231-233
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical characteristics of synchronous colorectal cancer are different according to tumour location. (2007)
  • Author(s): Fukatsu H., Kato J., Nasu J.I., Kawamoto H., Okada H., Yamamoto H., Sakaguchi K., Shiratori Y.
  • Journal Title: Dig Liver Dis. 39 Pages: 40-46
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Combination of 5-FU and IFNalpha enhances IFN signaling pathway and caspase-8 activity, resulting in marked apoptosis in hepatoma cell lines. (2006)
  • Author(s): Koike K, Takaki A, Tatsukawa M, Suzuki M, Shiraha H, Iwasaki Y, Sakaguchi K, Shiratori Y
  • Journal Title: Int J Oncol. 29・5 Pages: 1253-1261
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Early detection and quantification of lamivudine-resistant hepatitis B virus mutants by fluorescent biprobe hybridization assay in lamivudine-treated patients. (2006)
  • Author(s): Umeoka F, Iwasaki Y, Matsumura M, Takaki A, Kobashi H, Tatsukawa M, Shiraha H, Fujioka S, Sakaguchi K, Shiratori Y
  • Journal Title: J Gastroenterol. 41・7 Pages: 693-701
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contrast-enhanced ultrasonography depicts small tumor vessels for the evaluation of pancreatic tumors. (2006)
  • Author(s): Okamoto Y, Kawamoto H, Takaki A, Ishida E, Ogawa T, Kuwaki K, Kobayashi Y, Sakaguchi K, Shiratori Y
  • Journal Title: Eur J Radiol. 61・1 Pages: 163-169
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations. (2006)
  • Author(s): Hiraoka S, Kato J, Tatsukawa M, Harada K, Fujita H, Morikawa T, Shiraha H, Shiratori Y
  • Journal Title: Gastroenterology. 131・2 Pages: 379-389
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. (2006)
  • Author(s): Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y, Toshikuni N, Tanaka H, Miyake Y, Matsumoto E, Shiratori Y
  • Journal Title: Am J Gastroenterol. 101・9 Pages: 2038-2043
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. (2006)
  • Author(s): Tanaka H, Nouso K, Kobashi H, Kobayashi Y, Nakamura S, Miyake Y, Ohnishi H, Miyoshi K, Iwado S, Iwasaki Y, Sakaguchi K, Shiratori Y
  • Journal Title: Liver Int. 26・5 Pages: 543-551
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Combination of 5-FU and IFNalpha enhances IFN signaling pathway and caspase-8 activity, resulting in marked apoptosis in hepatoma cell lines. (2006)
  • Author(s): Koike K., Takaki A., Tatsukawa M., Suzuki M., Shiraha H., Iwasaki Y., Sakaguchi K., Shiratori Y.
  • Journal Title: Int J Oncol 29 Pages: 1253-1261
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Early detection and quantification of lamivudine-resistant hepatitis B virus mutants by fluorescent biprobe hybridization assay in lamivudine-treated patients. (2006)
  • Author(s): Umeoka F., Iwasaki Y., Matsumura M., Takaki A., Kobashi H., Tatsukawa M., Shiraha H., Fujioka S., Sakaguchi K., Shiratori Y.
  • Journal Title: J Gastroenterol. 41 Pages: 693-701
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations. (2006)
  • Author(s): Hiraoka S., Kato J., Tatsukawa M., Harada K., Fujita H., Morikawa T., Shiraha H.Shiratori Y.
  • Journal Title: Gastroenterology 131 Pages: 379-389
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. (2006)
  • Author(s): Nakamura S., Nouso K., Sakaguchi K., Ito Y.M., Ohashi Y., Kobayashi Y., Toshikuni N., Tanaka H., Miyake Y., Matsumoto E., Shiratori Y.
  • Journal Title: Am J Gastroenterol 101 Pages: 2038-2043
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Surveillance of hepatocellular carcinoma in patients with (2006)
  • Author(s): Tanaka H., Nouso K., Kobashi H., Kobayashi Y., Nakamura S., Miyake Y., Ohnishi H., Miyoshi K., Iwado S., Iwasaki, Y., Sakaguchi, K.Shiratori, Y.
  • Journal Title: Liver Int 26 Pages: 543-551
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antiviral therapy for cirrhotic hepatitis C : association with reduced hepatocellular carcinoma development and improved survival (2005)
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• [Journal Article] Des-{gamma}-carboxy Prothrombin Is a Potential Autologous Growth Factor for Hepatocellular Carcinoma (2005)
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• [Journal Article] Regression of hepatocellular carcinoma during vitamin K administration. (2005)
  • Author(s): Nouso K, Shiratori Y
  • Journal Title: World Journal of Gastroenterology 11・42 Pages: 6722-6724
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• [Journal Article] New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure. (2005)
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  • Journal Title: Tlansplantation 80・7 Pages: 930-936
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• [Journal Article] Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation. (2005)
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• [Journal Article] Antiviral therapy for cirrhotic hepatitis C : association witl reduced hepatocellular carcinoma development and improved survival. (2005)
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• [Journal Article] Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma. (2005)
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  • Journal Title: J Biol Chem 280 Pages: 6409-6415
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• [Journal Article] Regression of hepatocellular carcinoma during vitamin K administration. (2005)
  • Author(s): Nouso, K., Uematsu, S., Shiraga, K., Okamoto R., Harada R., Takayama S., Kawai W., Kimura S., Ueki T., Okano N., Nakagawa M., Mizuno M., Araki Y., Shiratori Y.
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• [Journal Article] New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure. (2005)
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  • Journal Title: Transplantation 80 Pages: 930-936
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation. (2005)
  • Author(s): Hanafusa T., Shinji T., Shiraha H., Nouso K., Iwasaki Y., Yumoto E., Ono T., Koide, N.
  • Journal Title: BMC Cancer 5, 9
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• [Journal Article] Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferon therapy (2004)
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• [Journal Article] Establishment of hepatitis C virus replicon cell lines possessing interferon-resistant phenotype (2004)
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  • Journal Title: Biochem.Biophys.Res.Commun. 323 Pages: 299-309
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• [Journal Article] Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation (2004)
  • Author(s): Otsuka, M., Shiratori, Y.et al.
  • Journal Title: Hepatology 40 Pages: 243-251
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• [Journal Article] Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferoi therapy. (2004)
  • Author(s): Iwasaki Y., Takaguchi K., Ikeda H., Makino Y., Araki Y, Ando M., Kobashi H., Kobatake T., Tanaka R., Tomita M.Senoh T., Kawaguchi M., Shimoe T., Manabe K., Kita K.Shimamura J., Sakaguchi K., Shiratori Y.
  • Journal Title: Liver Int. 24 Pages: 603-10
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• [Journal Article] Establishment of hepatitis C virus replicon cell lines possessing interferon-resistant phenotype. (2004)
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• [Journal Article] Vitamin K2 inhibits the growth and invasiveness o hepatocellular carcinoma cells via protein kinase A activation. (2004)
  • Author(s): Otsuka M., Kato N., Shao R.X., Hoshida Y., Ijichi H.Koike, Y., Taniguchi H., Moriyama M., Shiratori Y.Kawabe, T., Omata M.
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• [Book] 自然史からみた治療戦略 (2004)
  • Author(s): 白鳥 康史
  • Total Pages: 315
  • Publisher: 日本メディカルセンター
  • Description: 「研究成果報告書概要(和文)」より