Basic research for the study of NASP as a background of pancreatic cancer

• Project/Area Number: 16K15428
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: Kamada Yoshihiro 大阪大学, 医学系研究科, 准教授 (30622609)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: NASP / NASH / Mac-2 binding protein / 脂肪酸 / 膵線維化 / Mac-2bp / 慢性膵炎 / 膵がん

Outline of Final Research Achievements

We investigated the pathological change of pancreas in some mouse NASH models. Among these models, methionine choline deficient (MCD) diet administration induced inflammatory and fatty change in mouse pancreas as mouse steatohepatitis progression.
In human chronic pancreatitis patients, we found serum Mac-2 binding protein (Mac-2bp) as a useful biomarker for the diagnosis of chronic pancreatitis. We already have found that Mac-2bp is a useful biomarker for NASH in both human and mouse. Considering together, we hypothesize that Mac-2bp is a key molecule between NASH and NASP. To elucidate the role of Mac-2bp in NASH and NASP, we recently succeeded to establish Mac-2bp knockout mice.
Fatty acid (palmitic acid, oleic acid) induced inflammatory and fibrogenic cytokine production in pancreatic stellate cell, and this inflammatory and fibrogenic change accelerated the pathophysiological change of pancreatic cancer.

Research Products

• [Journal Article] Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma. (2018)
  • Author(s): Ogura S, Yoshida Y, Kurahashi T, Egawa M, Furuta K, Kiso S, Kamada Y, Hikita H, Eguchi H, Ogita H, Doki Y, Mori M, Tatsumi T, Takehara T.
  • Journal Title: Oncotarget Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of an antibody specific for cancer-associated haptoglobin: A possible implication of clinical investigation. (2018)
  • Author(s): Nishino K, Koda S, Kataoka N, Takamatsu S, Nakano M, Ikeda S, Kamamatsu Y, Morishita K, Moriwaki K, Eguchi H, Yamamoto E, Kikkawa F, Tomita Y, Kamada Y, Miyoshi E.
  • Journal Title: Oncotarget Volume: 9 Issue: 16 Pages: 12732-12744
  • DOI: 10.18632/oncotarget.24332
  • NAID: 120006799360
  • Peer Reviewed / Open Access
• [Journal Article] 肥満の及ぼす人体への影響～特にアディポサイトカイン～ (2018)
  • Author(s): 鎌田佳宏、三善英知、竹原徹郎
  • Journal Title: 消化器・肝臓内科 Volume: 3 Pages: 153-160
• [Journal Article] Fatty Acid-Mediated Stromal Reprogramming of Pancreatic Stellate Cells Induces Inflammation and Fibrosis That Fuels Pancreatic Cancer. (2017)
  • Author(s): Hata T, Kawamoto K, Eguchi H, Kamada Y, Takamatsu S, Maekawa T, Nagaoka S, Yamada D, Iwagami Y, Asaoka T, Noda T, Wada H, Gotoh K, Masamune A, Miyoshi E, Mori M, Doki Y.
  • Journal Title: Pancreas Volume: 46 Issue: 10 Pages: 1259-1266
  • DOI: 10.1097/mpa.0000000000000943
  • Peer Reviewed / Open Access
• [Journal Article] Mac-2 Binding Protein is a Useful Liver Fibrosis Biomarker for NAFLD/NASH (2017)
  • Author(s): Kamada Y and Miyoshi E.
  • Journal Title: Trends in Glycoscience and Glycotechnology Volume: 29 Issue: 170 Pages: E85-E92
  • DOI: 10.4052/tigg.1714.1E
  • NAID: 130006219286
  • ISSN: 0915-7352, 1883-2113
  • Peer Reviewed
• [Journal Article] Use of Mac-2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis. (2017)
  • Author(s): Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Yamada M, Mori K, Tanaka S, Maekawa T, Ebisutani Y, Yamamoto A, Takamatsu S, Yoneda M, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E.; Japan Study Group of NAFLD (JSG-NAFLD)
  • Journal Title: Hepatol Commun. Volume: 1 Issue: 8 Pages: 780-791
  • DOI: 10.1002/hep4.1080
  • Peer Reviewed / Open Access
• [Journal Article] Reevaluation of Pholiota squarrosa lectin-reactive haptoglobin as a pancreatic cancer biomarker using an improved ELISA system. (2017)
  • Author(s): Kusama K, Okamoto Y, Saito K, Kasahara T, Murata T, Ueno Y, Kobayashi Y, Kamada Y, Miyoshi E.
  • Journal Title: Glycoconj J. Volume: 34 Issue: 4 Pages: 537-544
  • DOI: 10.1007/s10719-017-9772-9
  • Peer Reviewed / Open Access
• [Journal Article] Serum WFA+ -M2BP levels predict liver fibrosis, development of hepatocellular carcinoma, and overall survival: A meta-analysis. (2017)
  • Author(s): Ito K, Murotani K, Nakade Y, Inoue T, Nakao H, Sumida Y, Kamada Y, Yoneda M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 12 Pages: 1922-1930
  • DOI: 10.1111/jgh.13802
  • Peer Reviewed
• [Journal Article] A novel pathogenesis of inflammatory bowel disease from the perspective of glyco-immunology. (2017)
  • Author(s): Shinzaki S, Iijima H, Fujii H, Kamada Y, Naka T, Takehara T, Miyoshi E.
  • Journal Title: J Biochem. Volume: 印刷中 Issue: 5 Pages: 409-415
  • DOI: 10.1093/jb/mvx010
  • Peer Reviewed
• [Journal Article] Development of alpha1,6-fucosyltransferase inhibitors through the diversity-oriented syntheses of GDP-fucose mimics using the coupling between alkyne and sulfonyl azide. (2017)
  • Author(s): Manabe, Y., Kasahara, S., Takakura, Y., Yang, X., Takamatsu, S., Kamada Y., Miyoshi, M., Yoshidome, D., Fukasea, K.
  • Journal Title: Bioorg. Med. Chem. Volume: in press Issue: 11 Pages: 2844-2850
  • DOI: 10.1016/j.bmc.2017.02.036
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma. (2017)
  • Author(s): Egawa M, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Furuta K, Kamada Y, Chatani N, Hamano M, Kiso S, Hikita H, Tatsumi T, Eguchi H, Nagano H, Doki Y, Mori M, Takehara T
  • Journal Title: Hepatol Res. Volume: 印刷中 Issue: 11 Pages: 1196-1205
  • DOI: 10.1111/hepr.12854
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] メタボがんの高危険群囲い込みのための血液バイオマーカーによる非侵襲的診断方法開発 (2017)
  • Author(s): 鎌田佳宏、三善英知
  • Journal Title: 臨床病理 Volume: 7 Pages: 778-785
  • Peer Reviewed
• [Journal Article] 肝疾患の糖鎖バイオマーカー (2017)
  • Author(s): 鎌田佳宏、三善英知
  • Journal Title: BIO Clinica Volume: 4 Pages: 33-37
• [Journal Article] Establishment of mouse Mac-2 binding protein enzyme-linked immunosorbent assay and its application for mouse chronic liver disease models. (2016)
  • Author(s): Iwata A, Kamada Y, Ebisutani Y, Yamamoto A, Ueda Y, Arai H, Fujii H, Takamatsu S, Maruyama N, Maeda M, Takehara T, Miyoshi E.
  • Journal Title: Hepatology Research Volume: 47 Issue: 9 Pages: 1-11
  • DOI: 10.1111/hepr.12819
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly. (2016)
  • Author(s): Kamada Y, Kida S, Hirano KI, Yamaguchi S, Suzuki A, Hashimoto C, Kimura A, Sato M, Fujii H, Sobajima T, Yamamoto A, Ebisutani Y, Takamatsu S, Shinzaki S, Yoshida Y, Yamada M, Nagasaka H, Takehara T, Miyoshi E.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 311 Issue: 5 Pages: G859-G868
  • DOI: 10.1152/ajpgi.00231.2016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Application of glyco-science to the early detection of pancreatic cancer. (2016)
  • Author(s): Miyoshi E, Kamada Y
  • Journal Title: Cancer Sci Volume: 107 Issue: 10 Pages: 1357-1362
  • DOI: 10.1111/cas.13011
  • Peer Reviewed / Open Access
• [Journal Article] Core-fucosylation plays a pivotal role in hepatitis B pseudo virus infection: a possible implication for HBV glycotherapy. (2016)
  • Author(s): Takamatsu S, Shimomura M, Kamada Y, Maeda H, Sobajima T, Hikita H, Iijima M, Okamoto Y, Misaki R, Fujiyama K, Nagamori S, Kanai Y, Takehara T, Ueda K, Kuroda S, Miyoshi E.
  • Journal Title: Glycobiology. Volume: 26 Pages: 1180-1189
  • DOI: 10.1093/glycob/cww067
  • Peer Reviewed
• [Journal Article] Serum Mac-2 binding protein is a novel biomarker for chronic pancreatitis. (2016)
  • Author(s): Maekawa T*, Kamada Y* (equally contributed), Ebisutani Y, Ueda M, Hata T, Kawamoto K, Takamatsu S, Mizutani K, Shimomura M, Sobajima T, Fujii H, Nakayama K, Nishino K, Yamada M, Kumada T, Ito T, Eguchi H, Nagano H, Miyoshi E.
  • Journal Title: World J Gastroenterol Volume: 22 Issue: 17 Pages: 4403-10
  • DOI: 10.3748/wjg.v22.i17.4403
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Core Fucosylation on T cells, Required for Activation of T-cell Receptor Signaling and Induction of Colitis in Mice, is Increased in Patients with Inflammatory Bowel Disease. (2016)
  • Author(s): Fujii H, Shinzaki S, Iijima H, Wakamatsu K, Iwamoto C, Sobajima T, Kuwahara R, Hiyama S, Hayashi Y, Takamatsu S, Uozumi N, Kamada Y, Tsujii M, Taniguchi N, Takehara T, Miyoshi E
  • Journal Title: Gastroenterology Volume: 未定 Issue: 7 Pages: 00297-3
  • DOI: 10.1053/j.gastro.2016.03.002
  • NAID: 40021255019
  • Peer Reviewed
• [Journal Article] A glycoproteomic approach to identify novel glycomarkers for cancer stem cells. (2016)
  • Author(s): Sawanobori A, Moriwaki K, Takamatsu S, Kamada Y, Miyoshi E.
  • Journal Title: Proteomics Volume: 16 Issue: 24 Pages: 3073-3080
  • DOI: 10.1002/pmic.201500472
  • Peer Reviewed
• [Journal Article] Site-specific and linkage analyses of fucosylated N-glycans on haptoglobin in sera of patients with various types of cancer: possible implication for the differential diagnosis of cancer. (2016)
  • Author(s): Takahashi S, Sugiyama T, Shimomura M, Kamada Y, Fujita K, Nonomura N, Miyoshi E, Nakano M.
  • Journal Title: Glycoconj J Volume: 33 Issue: 3 Pages: 471-82
  • DOI: 10.1007/s10719-016-9653-7
  • Peer Reviewed / Open Access
• [Journal Article] Specific increase in serum core-fucosylated haptoglobin in patients with chronic pancreatitis. (2016)
  • Author(s): Ueda M, Kamada Y, Takamatsu S, Shimomura M, Maekawa T, Sobajima T, Fujii H, Nakayama K, Nishino K, Yamada M, Kobayashi Y, Kumada T, Ito T, Eguchi H, Nagano H, Miyoshi E.
  • Journal Title: Pancreatology Volume: 16 Issue: 2 Pages: 238-243
  • DOI: 10.1016/j.pan.2016.01.004
  • Peer Reviewed
• [Journal Article] Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice. (2016)
  • Author(s): Furuta K, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Maeda S, Egawa M, Chatani N, Nishida K, Nakaoka Y, Kiso S, Kamada Y, Takehara T.
  • Journal Title: Hepatology Volume: 63 Issue: 4 Pages: 1340-1355
  • DOI: 10.1002/hep.28410
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Elevation of CA19-9-Related Novel Marker, Core 1 Sialyl Lewis A, in Sera of Adenocarcinoma Patients Verified by a SRM-Based Method. (2016)
  • Author(s): Tanaka-Okamoto M, Yabu M, Mukai M, Takahashi H, Fujiwara Y, Ohue M, Kamada Y, Miyoshi E, Miyamoto Y.
  • Journal Title: Journal of Proteome Research Volume: 15 Issue: 1 Pages: 152-165
  • DOI: 10.1021/acs.jproteome.5b00893
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. (2016)
  • Author(s): Tokushige K, Hyogo H, Nakajima T, Ono M, Kawaguchi T, Honda K, Eguchi Y, Nozaki Y, Kawanaka M, Tanaka S, Imajo K, Sumida Y, Kamada Y, Fujii H, Suzuki Y, Kogiso T, Karino Y, Munekage K, Kuromatsu R, Oeda S, Yanase M, Mori K, Ogawa Y, Seko Y, Takehara T, Itoh Y, Nakajima A, Kanemasa K, Saibara T
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 6 Pages: 586-96
  • DOI: 10.1007/s00535-015-1129-1
  • Peer Reviewed / Open Access
• [Journal Article] Role of aberrant IgG glycosylation in the pathogenesis of inflammatory bowel disease. (2016)
  • Author(s): Miyoshi E, Shinzaki S, Fujii H, Iijima H, Kamada Y, Takehara T.
  • Journal Title: Proteomics Clinical Applications Volume: 未定 Issue: 4 Pages: 384-390
  • DOI: 10.1002/prca.201500089
  • Peer Reviewed
• [Journal Article] N-Acetylglucosaminyltransferase V exacerbates murine colitis with macrophage dysfunction and enhances colitic tumorigenesis. (2016)
  • Author(s): Shinzaki S, Ishii M, Fujii H, Iijima H, Wakamatsu K, Kawai S, Shiraishi E, Hiyama S, Inoue T, Hayashi Y, Kuwahara R, Takamatsu S, Kamada Y, Morii E, Tsujii M, Takehara T, Miyoshi E.
  • Journal Title: J Gastroenterol. Volume: 51 Issue: 4 Pages: 357-369
  • DOI: 10.1007/s00535-015-1119-3
  • Peer Reviewed
• [Journal Article] Ectopic expression of N-acetylglucosaminyltransferase V accelerates hepatic triglyceride synthesis. (2016)
  • Author(s): Kamada Y, Ebisutani Y, Kida S, Mizutani K, Akita M, Yamamoto A, Fujii H, Sobajima T, Terao N, Takamatsu S, Yoshida Y, Takehara T, Miyoshi E
  • Journal Title: Hepatol Res. Volume: 46 Issue: 3 Pages: 1189-129
  • DOI: 10.1111/hepr.12541
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Impact of plasma transaminase levels on the peripheral blood glutamate levels and memory functions in healthy subjects. (2015)
  • Author(s): Kamada Y, Hashimoto R, Yamamori H, Yasuda Y, Takehara T, Fujita Y, Hashimoto K, Miyoshi E.
  • Journal Title: BBA Clin Volume: 5 Pages: 101-107
  • DOI: 10.1016/j.bbacli.2016.02.004
  • Peer Reviewed
• [Presentation] マウスMac-2bpの測定系開発と発現制御に関する検討 (2017)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] Biomarkers for NAFLD/NASH (2017)
  • Author(s): Yoshihiro Kamada, Tetsuo Takehara, Eiji Miyoshi
  • Organizer: The 103rd General Meeting of the Japanese Society of Gastroenterology
  • Int'l Joint Research / Invited
• [Presentation] NAFLD病態進展におけるMac-2 binding proteinの意義について (2017)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] NAFLD診断におけるMac-2 binding proteinの有用性について (2017)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 日本消化器病学会近畿支部第107回例会
• [Presentation] NASH診療におけるMac-2 binding proteinとM2BPGiの比較検討 (2017)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: JDDW 2017
• [Presentation] コアフコシル化の肝細胞コレステロール代謝における役割 (2017)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第42回日本肝臓学会西部会
• [Presentation] 7.Establishment of mouse Mac-2 binding protein ELISA and its application for mouse chronic liver disease models. (2017)
  • Author(s): Yoshihiro Kamada, Ayumi Iwata, Yusuke Ebisutani, Akiko Yamamoto, Yui Ueda, Hitomi Arai, Hironobu Fujii, Shinji Takamatsu, Nobuhiro Maruyama, Masahiro Maeda, Tetsuo Takehara, Eiji Miyoshi
  • Organizer: The 68 th Annual Meeting of the American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] コアフコースを標的とした糖鎖治療法開発の基礎的検討 (2016)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第41回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル 東京
  • Year and Date: 2016-12-08
• [Presentation] Impact of plasma transaminase levels on the peripheral blood glutamate levels and memory functions in healthy subjects (2016)
  • Author(s): Yoshihiro Kamada, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Tetsuo Takehara, Yuko Fujita, Kenji Hashimoto, Eiji Miyoshi
  • Organizer: The 67 th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Roles of Mac-2 binding protein in the NASH liver fibrosis progression (2016)
  • Author(s): Yusuke Ebisutani, Yoshihiro Kamada, Akiko Yamamoto, Shun Ikeda, Hitomi Arai, Ayumi Iwata, Eiji Miyoshi. et al.
  • Organizer: The 67 th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Mac-2 binding proteinのNASHバイオマーカーとしての意義 (2016)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: JDDW 2016
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2016-11-03
• [Presentation] 膵がん、慢性膵炎に対する新規糖鎖バイオマーカーの開発 (2016)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: JDDW 2016
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2016-11-03
• [Presentation] コアフコシル化を標的とした新規NASH治療法の開発の基礎的検討 (2016)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: JDDW 2016
  • Place of Presentation: 神戸国際会議場 神戸
  • Year and Date: 2016-11-03
• [Presentation] 炎症性腸疾患の新しい病態解明から臨床糖鎖免疫学の創成 (2016)
  • Author(s): 鎌田佳宏、三善英知
  • Organizer: 第35回日本糖質学会年会
  • Place of Presentation: 高知市文化プラザかるぽーと 高知
  • Year and Date: 2016-09-01
• [Presentation] 血液糖鎖バイオマーカーを使ったBallooning hepatocyteの診断予測 (2016)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張 千葉
  • Year and Date: 2016-05-19
• [Presentation] レクチンを用いた新規NASH治療法開発への基礎的検討 (2016)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル 東京
  • Year and Date: 2016-04-21