Aberrant fucosylation of cancer in Gastroenterology and hepatology and its mechanisms

• Project/Area Number: 16590245
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Osaka University
• Principal Investigator: MIYOSHI Eiji Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (20322183)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,100,000 (Direct Cost: ¥3,100,000); Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: hepatoma / fucosylation / sugar chain / GDP-fucose / haptoglobin / Fut8 / receptor / AFP-L3 / GDP-fucose / がん / 腫瘍マーカー / 糖転移酵素 / グライコミクス / FUT8 / FX / AFP

Research Abstract

Changes in oligosaccharide structures have been reported in certain types of malignant transformations and, thus could be used for tumor markers in certain types of cancer. In the case of pancreatic cancer cell lines, a variety of fucosylated proteins are secreted into their conditioned media. To identify fucosylated proteins in the serum of patients with pancreatic cancer, we performed western blot analyses using Aleuria Aurantica Lectin (AAL), which is specific for fucosylated structures. An approximately 40 kD protein was found to be highly fucosylated in pancreatic cancer and an N-terminal analysis revealed that it was the beta chain of haptoglobin. While the appearance of fucosylated haptoglobin has been reported in other diseases such as hepatocellular carcinoma, liver cirrhosis, gastric cancer and colon cancer, the incidence was significantly higher in the case of pancreatic cancer. Fucosylated haptoglobin was observed more frequently at the advanced stage of pancreatic cancer and disappeared after an operation. A mass spectrometry analysis of haptoglobin purified from the serum of patients with pancreatic cancer and the medium from a pancreatic cancer cell line, PSN-1 showed that the alpha 1-3/alpha1-4/alpha 1-6 fucosylation of haptoglobin was increased in pancreatic cancer. When a hepatoma cell line, Hep3B was cultured with the conditioned media from pancreatic cancer cells, haptoglobin secretion was dramatically increased. These findings suggest that fucosylated haptoglobin could serve as a novel marker for pancreatic cancer. Two possibilities were considered in terms of the fucosylation of haptoglobin. One is that pancreatic cancer cells, themselves, produce fucosylated haptoglobin ; the other is that pancreatic cancer produces a factor, which induces the production of fucosylated haptoglobin in the liver.

Research Products

• [Journal Article] Core fucosylation regulates EGF receptor-mediated intracellular signaling. (2006)
  • Author(s): Wang X et al.
  • Journal Title: J.Biol.Chem. 281(5) Pages: 2572-2577
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of core fucosylation of low-density lipoprotein receptor-related protein-1 impairs its function, leading to the upregulation of serum levels of insulin-like growth factor-bindgin protein 3 in Fut8-/- mice. (2006)
  • Author(s): Lee SH et al.
  • Journal Title: J.Biochem 139(3) Pages: 391-398
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Aberrant expression of N-Acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreatic cancer. (2006)
  • Author(s): Ide Y et al.
  • Journal Title: Biochem Biophys Res Commun 341(2) Pages: 478-482
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High expression of N-acetylglucosaminyltransferase V in favorable neuroblastomas : Involvement of its effect on apoptosis. (2006)
  • Author(s): Inamori K et al.
  • Journal Title: FEBS Letters 580 Pages: 627-632
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A specific detection of GlcNAc beta1-6 Man alpha1-branches in N-linked glycoproteins based on the N-acetylglucosaminyltransferase VI. (2006)
  • Author(s): Watanabe T et al.
  • Journal Title: Glycobiology 16(5) Pages: 431-439
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Co-expression of matriptase and N-acetylglucosaminyltransferase V in thyroid cancer tissues ; its possible role in prolonged stability in vivo by aberrant glycosylation. (2006)
  • Author(s): Ito Y et al.
  • Journal Title: Glycobiology 16(5) Pages: 368-374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Core fucosylation regulates EGF receptor-mediated intracellular signaling. (2006)
  • Author(s): Wang X, Gu J, Ihara H, Miyoshi E, Honke K, Taniguchi N.
  • Journal Title: J.Biol.Chem. 281(5) Pages: 2572-2577
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of core fucosylation of low-density lipoprotein receptor-related protein-1 impairs its function, leading to the upregulation of serum levels of insulin-like growth factor-bindgin protein 3 in Fut8-/-mice. (2006)
  • Author(s): Lee SH., Takahashi M, Honke, K, Miyoshi E, Osumi D, Sakiyama H, Ekuni A, Wang X, Inoue S, Gu J, Kadomatsu K, Taniguchi N.
  • Journal Title: J.Biochem, 139(3) Pages: 391-398
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High expression of N-acetylglucosaminyltransferase V in favorable neuroblastomas : Involvement of its effect on apoptosis. (2006)
  • Author(s): Inamori K, Gu J, Ohira M, Kawasaki A, Nakamura Y, Nakagawa T, Kondo A, Miyoshi E, Nakagawara A, Taniguchi N.
  • Journal Title: FEBS Letters 580 Pages: 627-632
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (2006) A specific detection of GlcNAc beta1-6 Man alpha1-branches in N-linked glycoproteins based on the N-acetylglucosaminyltransferase VI. (2006)
  • Author(s): Watanabe T, Ihara H, Miyoshi E, Honke K, Taniguchi N, Taguchi T.
  • Journal Title: Glycobiology 16(5) Pages: 431-439
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Co-expression of matriptase and N-acetylglucosaminyltransferase V in thyroid cancer tissues ; its possible role in prolonged stability in vivo by aberrant glycosylation. (2006)
  • Author(s): Ito Y, Akinaga A, Yamanaka K, Nakagawa T, Kondo A, Dickson R B, Lin C-Y, Miyauchi A, Taniguchi N, Miyoshi E.
  • Journal Title: Glycobiology 16(5) Pages: 368-374
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fucosylated haptoglobin is a novel marker for pancreatic cancer : A detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation. (2006)
  • Author(s): Noriko Okuyama
  • Journal Title: Int.J.Cancer 108(In press)
• [Journal Article] In vivo cleavage of alpha 2,6-sialyltransferase by Alzheimer's beta-secretase (2005)
  • Author(s): Kitazume S et al.
  • Journal Title: J Biol Chem. 280(9) Pages: 8589-8595
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Elevated expression of N-acetylglucosaminyltransferase V in first trimester human placenta. (2005)
  • Author(s): Tomiie M et al.
  • Journal Title: Biochem Biophys Res Commun. 330(3) Pages: 999-1004
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Core fucosylation of N-linked glycans in Leukocyte Adhesion Deficiency/Congenital Disorder of Glycosylation IIc (LAD II/CDG IIc) fibroblasts. (2005)
  • Author(s): Sturla L et al.
  • Journal Title: Glycobiology 15(10) Pages: 924-934
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bisecting GlcNAc Mediates the Binding of Annexin V to Hsp47. (2005)
  • Author(s): Gao CX et al.
  • Journal Title: Glycobiology 15(11) Pages: 1067-1075
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of N-Acetylglucosaminyltransferase V in the development of human esophageal cancers : immunohistochemical data from carcinomas and nearby non-cancerous lesions. (2005)
  • Author(s): Ishibashi Y et al.
  • Journal Title: Oncology 69(4) Pages: 301-310
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice. (2005)
  • Author(s): Wang X et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA 102(44) Pages: 15791-15796
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of target proteins of N-acetylglucosaminyltransferase V in human colon cancer and implication of protein tyrosine phosphatase kappa in enhanced cancer cell migration. (2005)
  • Author(s): Kim YS et al.
  • Journal Title: Proteomics 6(4) Pages: 1187-1191
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fucosylated haptoglobin is a novel marker for pancreatic cancer : A detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation. (2005)
  • Author(s): Okuyama N et al.
  • Journal Title: Int.J.Cancer 118(11) Pages: 2803-2808
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In vivo cleavage of alpha 2,6-sialyltransferase by Alzheimer's beta-secretase. (2005)
  • Author(s): Kitazume S, Nakagawa K, Oka R, Tachida Y, Ogawa K, Luo Y, Citron M, Shitara H, Taya C, Yonekawa H, Paulson JC, Miyoshi E, Taniguchi N, Hashimoto Y.
  • Journal Title: J Biol Chem. 280(9) Pages: 8589-8595
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Elevated expression of N-acetylglucosaminyltransferase V in first trimester human placenta. (2005)
  • Author(s): Tomiie M, Isaka S, Miyoshi E, Taniguchi N, Kimura T, Ogita K, Tsutsui T, Shimoya K, Nakagawa T, Kondo A, Koyama M, Murata Y.
  • Journal Title: Biochem Biophys Res Commun. 330(3) Pages: 999-1004
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Core fucosylation of N-linked glycans in Leukocyte Adhesion Deficiency/Congenital Disorder of Glycosylation IIc (LAD II/CDG IIc) fibroblasts. (2005)
  • Author(s): Sturla L, Fruscione F, Noda K, Miyoshi E, Taniguchi N, Contini P, Tonetti M.
  • Journal Title: Glycobiology 15(10) Pages: 924-934
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bisecting GlcNAc Mediates the Binding of Annexin V to Hsp47. (2005)
  • Author(s): Gao CX, Miyoshi E, Uozumi N, Takamiya R, Wang X, Noda K, Gu J, Honke K, Wada Y, Taniguchi N.
  • Journal Title: Glycobiology 15(11) Pages: 1067-1075
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of N-Acetylglucosaminyltransferase V in the development of human esophageal cancers : immunohistochemical data from carcinomas and nearby non-cancerous lesions. (2005)
  • Author(s): Ishibashi Y, Dosaka-Akita H, Miyoshi E, Shindoh M, Miyamoto M, Kinoshita I, Miyazaki H, Itoh T, Kondo S, Nishimura M, Taniguchi N.
  • Journal Title: Oncology 69(4) Pages: 301-310
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice. (2005)
  • Author(s): Wang X, Inoue S, Gu J, Miyoshi E, Noda K, Li W, Mizuno-Horikawa Y, Nalano M, Asahi M, Takahashi M, Uozumi N, Lee S H, Ikeda Y, Yamaguchi Y, Aze Y, Tomiyama Y, Fujii J, Suzuki K, Kondo A, Shapiro S D, Lopez-Otin C, Kuwaki T, Okabe M, Honke K, Taniguchi N.
  • Journal Title: Proc.Natl.Acad.Sci.USA 102(44) Pages: 15791-15796
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of target proteins of N-acetylglucosaminyl-transferase V in human colon cancer and implication of protein tyrosine phosphatase kappa in enhanced cancer cell migration. (2005)
  • Author(s): Kim YS, Kang HY, Kim JY, Oh S, Kim CH, Ryu CJ, Miyoshi E, Taniguchi N, Ko JH.
  • Journal Title: Proteomics 6(4) Pages: 1187-1191
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fucosylated haptoglobin is a novel marker for pancreatic cancer : A detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation. (2005)
  • Author(s): Okuyama N, Ide Y, Nakano M, Nakagawa T, Yamanaka K, Moriwaki K, Murata K, Ohigashi H, Yokoyama S, Eguchi H, Ishikawa O, Ito T, Kato M, Kasahara A, Kawano S, Gu J, Taniguchi N, Miyoshi E.
  • Journal Title: Int.J.Cancer 118(11) Pages: 2803-2808
  • NAID: 130006995325
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Core fucosylation regulates FEG receptor-mediated intracellular signaling. (2005)
  • Author(s): Xiangchun Wang
  • Journal Title: J Biol Chem 281(5) Pages: 2572-2577
• [Journal Article] Core fucosylation of N-linked glycans in Leukocyte Adhesion Deficiency/Congenital Disorder of Glycosylation IIc(LAD II/CDG IIc) fibroblasts. (2005)
  • Author(s): Laura Sturla
  • Journal Title: Glycobiology 15(10) Pages: 924-925
• [Journal Article] Bisecting GIcNAc Mediates the Binding of Annexin V to Hsp47. (2005)
  • Author(s): Cong-xiao Gao
  • Journal Title: Glycobiology 15(11) Pages: 1067-1075
• [Journal Article] In vivo cleavage of alpha 2,6-sialyltransferase by Alzheimer's beta-secretase. (2005)
  • Author(s): Shinobu Kitazume
  • Journal Title: J Biol Chem 280(9) Pages: 6589-6595
• [Journal Article] Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice. (2005)
  • Author(s): Xiangchun Wang
  • Journal Title: Proc.Natl.Acad.Sci.U S A 102(4) Pages: 15791-15796
• [Journal Article] In vivo cleavage of α 2,6-sialyltransferase by Alzheimer's β-secretase. (2005)
  • Author(s): Kitazume, S
  • Journal Title: J Biol Chem. 280(In press)
• [Journal Article] N-acetylglucosaminyltransferase IX acts on the GlcNAcbeta 1,2-Manalpha 1-Ser/Thr moiety, forming alpha 2,6-branched structure in brain O-mannosyl glycan. (2004)
  • Author(s): Inamori KI et al.
  • Journal Title: J Biol Chem 279(4) Pages: 2337-2340
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of N-acetylglucosaminiyltranseferase V in non-small cell lung cancers : its association with prognosis and histology. (2004)
  • Author(s): Akita HD et al.
  • Journal Title: Clninical Cancer Res. 10(5) Pages: 1773-1779
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Addition of β 1-6 GlcNAc branching on matriptase increases the stability to degradation, especially via the Asn 772 site. (2004)
  • Author(s): Ihara S et al.
  • Journal Title: Glycobiology 14(2) Pages: 139-146
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] β1,4-N-acetylglucosaminyltransferase III down-regulates neutrite outgrowth induced by co-stimulation of epidermal growth factor and integrins through the Ras/ERK signaling pathway in PC12 cells. (2004)
  • Author(s): Gu J et al.
  • Journal Title: Glycobiology 14(2) Pages: 177-186
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Introduction of bisecting GlcNAc into integrin alpha 5beta 1 reduces ligand binding and down-regulates cell adhesion and cell migration. (2004)
  • Author(s): Isaji T et al.
  • Journal Title: J Biol Chem. 279(19) Pages: 19747-19754
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Attachment of human colon cancer cells to vascular endothelium is enhanced by N-acetylglucosaminyltransferase V. (2004)
  • Author(s): Murata K et al.
  • Journal Title: Oncology 66(6) Pages: 492-501
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of target proteins of N-acetylglucosaminyl-transferase V and fucosyltransferase 8 in human gastric tissues by glycomic approach. (2004)
  • Author(s): Kim YS et al.
  • Journal Title: Proteomics 4(11) Pages: 3353-3358
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] N-acetylglucosaminyltransferase IX acts on the GlcNAcbeta 1,2-Manalpha 1-Ser/Thr moiety, forming alpha 2,6-branched structure in brain 0-mannosyl glycan. (2004)
  • Author(s): Inamori KI, Endo T, Gu J, Matsuo I, Ito Y, Fujii S, Iwasaki H, Narimatsu H, Miyoshi E. Honke K, Taniguchi N.
  • Journal Title: J Biolt Chem. 279(4) Pages: 2337-2340
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of N-acetylglucosaminiyltranseferase V in non-small cell lung cancers : its association-with prognosis and histology. (2004)
  • Author(s): Akita H D, Miyoshi E, Suzuki O, Itoh T, Kinoshita I, Yamazaki K, Nishimura M, Katoh H, Taniguchi N.
  • Journal Title: Clinical Cancer Res. 10(5) Pages: 1773-1779
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Polo-like kinase 1 overexpression is an early event in the progression of papillary carcinoma. (2004)
  • Author(s): Ito Y, Miyoshi E, Sasaki N, Kakudo K, Yoshida H, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Matsuura N, Kuma K, Miyauchi A.
  • Journal Title: Br J Cancer 90(2) Pages: 414-418
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Addition of β 1-6 GlcNAc branching on matriptase increases the stability to degradation, especially via the Asn 772 site. (2004)
  • Author(s): Ihara S, Miyoshi E, Nakahara S, Sakiyama H, Ihara H, Honke K, Dickson R B, Lin C Y, Taniguchi N.
  • Journal Title: Glycobiology 14(2) Pages: 139-146
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] β1,4-N-acetylglucosaminyltransferase III down-regulates neutrite outgrowth induced by co-stimulation of epidermal growth factor and integrins through the Ras/ERK signaling pathway in PC12 cells. (2004)
  • Author(s): Gu J, Zhao Y, Isaji T, Shibukawa Y, Ihara H, Takahashi M, Ikeda Y, Miyoshi E, Honke K, Taniguchi N.
  • Journal Title: Glycobiology 14(2) Pages: 177-186
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Attachment of human colon cancer cells to vascular endothelium is enhanced by N-acetylglucosaminyltransferase V. (2004)
  • Author(s): Murata K, Miyoshi E, Ihara S, Noura S, Kameyama M, Ishikawa O, Doki Y, Yamada T, Ohigashi H, Sasaki Y, Higashiyama M, Tarui T, Takada Y, Kannagi R, Taniguchi N, Imaoka S.
  • Journal Title: Oncology 66(69) Pages: 492-501
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of target proteins of N-acetylglucosaminyl-transferase V and fucosyltransferase 8 in human gastric tissues by glycomic approach. (2004)
  • Author(s): Kim YS, Hwang SY, Oh S, Sohn H, Kang HY, Lee JH, Cho EW, Kim JY, Yoo JS, Kim NS, Kim CH, Miyoshi E, Taniguchi N, Ko JH.
  • Journal Title: Proteomics 4(11) Pages: 3353-3358
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] N-acetylglucosaminyltransferase IX acts on the GlcNAcbeta 1,2-Manalpha 1-Ser/Thr moiety, forming α2,6-branched structure in brain O-mannosyl glycan (2004)
  • Author(s): Inamori, KI
  • Journal Title: J Biol Chem. 279(4) Pages: 2337-2340
• [Journal Article] Expression of N-acetylglucosaminiyltranseferase V in non-small cell lung cancers : its association with prognosis and histology (2004)
  • Author(s): Akita, H D
  • Journal Title: Clninical Cancer Res. 10(5) Pages: 1773-1779
• [Journal Article] Polo-like kinase 1 overexpression is an early event in the progression of papillary carcinoma. (2004)
  • Author(s): Ito, Y
  • Journal Title: Br J Cancer 90(2) Pages: 414-418
• [Journal Article] Addition of β1-6 GlcNAc branching on matriptase increases the stability to degradation, especially via the Asn 772 site (2004)
  • Author(s): Ihara, S
  • Journal Title: Glycobiology 14(2) Pages: 139-146
• [Journal Article] Introduction of bisecting GlcNAc into integrin α5β 1 reduces ligand binding and down-regulates cell adhesion and cell migration (2004)
  • Author(s): Isaji, T
  • Journal Title: J Biol Chem. 279(19) Pages: 19747-19754
• [Book] 遺伝医学 糖鎖と癌の浸潤・転移 (2005)
  • Author(s): 三善英知et al.
  • Total Pages: 6
  • Publisher: メディカルドゥ
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 未来を拓く糖鎖科学 癌とフコシル化 (2005)
  • Author(s): 三善英知et al.
  • Total Pages: 5
  • Publisher: 金芳堂
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 糖鎖科学の新展開 肝炎、肝がんと糖鎖 (2005)
  • Author(s): 三善英知et al.
  • Total Pages: 7
  • Publisher: NTS
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] α1-6フコシル化特異的レクチン (2005)
  • Inventor(s): 秦 洋二, 谷口 直之, 三善 英知, 顧 建国, 山本 憲二
  • Industrial Property Rights Holder: 月桂冠
  • Industrial Property Number: 2005-358545
  • Filing Date: 2005-12-13
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 血管新生作用を有する糖転移酵素GnT-V (2004)
  • Inventor(s): 谷口 直之, 三善 英知, 斉藤 貴志
  • Industrial Property Rights Holder: サントリー
  • Filing Date: 2004-07-07
  • Description: 「研究成果報告書概要(和文)」より