New humoral factor facilitates hepato-biliary and pancreatic cancer progression and development of innovative thrapy

• Project/Area Number: 18H02877
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Gunma University
• Principal Investigator: Shirabe Ken 群馬大学, 大学院医学系研究科, 教授 (70264025)
• Co-Investigator(Kenkyū-buntansha): 播本 憲史 群馬大学, 医学部附属病院, 講師 (00419582) ; 石井 範洋 群馬大学, 医学部附属病院, 助教 (00711508) ; 久保 憲生 群馬大学, 医学部附属病院, 助教 (10464744) ; 五十嵐 隆通 群馬大学, 医学部附属病院, 助教 (20648472) ; 市川 聡 北海道大学, 薬学研究院, 教授 (60333621) ; 横堀 武彦 群馬大学, 未来先端研究機構, 准教授 (60420098) ; 新木 健一郎 群馬大学, 大学院医学系研究科, 助教 (60431706) ; 渡辺 亮 群馬大学, 医学部附属病院, 助教 (60738847) ; 塚越 真梨子 群馬大学, 大学院医学系研究科, 助教 (60781317)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 肝胆膵がん / 癌関連線維芽細胞 / M2BPGi / 肝胆膵癌 / マウス皮下腫瘍モデル / Galectin 3阻害剤

Outline of Final Research Achievements

M2BPGi and galectin-3 proteins co-localised in HCC cells, while M2BP mRNA was detected in cirrhotic liver stromal cells. mTOR signaling was upregulated in M2BPGi-treated HCC cells. Moreover, M2BPGi treatment induced tumour-promoting effects on HCC in vitro by activated mTOR signaling. In addition, M2BPGi bound to galectin-3 to induce membranous galectin-3 expression in HCC cells. In vivo, M2BPGi enhanced the growth of xenografted HCC. M2BPGi is produced in stromal cells of the cirrhotic liver. Furthermore, M2BPGi enhances the progression of HCC through the galectin-3/mTOR pathway. Therefore, galectin 3 inhibitor would be quite effective in M2BPGi. We have already developed the prototype galectin 3 inhibitor and we are now on the way of new galectin 3 inhibitor production, which has extremely high affinity to galectin 3.

Academic Significance and Societal Importance of the Research Achievements

難治癌の代表とされる肝胆膵がんの増殖進展において癌関連線維芽細胞が重要な役割を担っていることが明らかになった。さらに癌関連線維芽細胞と癌細胞の連関においてM2BPGiという肝線維化の新規血清マーカーが癌関連線維芽細胞や肝硬変の星細胞で産生され、癌細胞の増殖・進展を促進する新たな分子機序が明らかになった。その連関を遮断するgalectin 3阻害剤の有用性が示唆された。

Research Products

• [Journal Article] Hepatic stellate cell as a Mac-2-binding protein-producing cell in patients with liver fibrosis (2021)
  • Author(s): Gantumur D, Harimoto N, Muranushi R, Hoshino K, Batbayar C, Hagiwara K, Yamanaka T, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Araki K, Yokobori T, Aishima S, Shirabe K.
  • Journal Title: Hepatol Res . Volume: Online ahead of print. Issue: 10 Pages: 1058-1063
  • DOI: 10.1111/hepr.13648
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein-coupled Receptor 68 (2021)
  • Author(s): Yamanaka T, Harimoto N, Yokobori T, Muranushi R, Hoshino K, Hagiwara K, Gantumur D, Handa T, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Araki K, Umezawa K, Shirabe K.
  • Journal Title: Mol Cancer Ther. Volume: Online ahead of print. Issue: 6 Pages: 1019-1028
  • DOI: 10.1158/1535-7163.mct-20-0150
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling (2020)
  • Author(s): Dolgormaa Gantumur、Harimoto Norifumi、Ishii Norihiro、Yamanaka Takahiro、Hagiwara Kei、Tsukagoshi Mariko、Igarashi Takamichi、Watanabe Akira、Kubo Norio、Araki Kenichiro、Handa Tadashi、Yokobori Takehiko、Oyama Tetsunari、Kuwano Hiroyuki、Shirabe Ken
  • Journal Title: British Journal of Cancer Volume: 123 Issue: 7 Pages: 1145-1153
  • DOI: 10.1038/s41416-020-0971-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts (2020)
  • Author(s): Yamanaka Takahiro、Harimoto Norifumi、Yokobori Takehiko、Muranushi Ryo、Hoshino Kouki、Hagiwara Kei、Gantumur Dolgormaa、Handa Tadashi、Ishii Norihiro、Tsukagoshi Mariko、Igarashi Takamichi、Tanaka Hiroshi、Watanabe Akira、Kubo Norio、Araki Kenichiro、Shirabe Ken
  • Journal Title: British Journal of Cancer Volume: 122 Issue: 7 Pages: 986-994
  • DOI: 10.1038/s41416-020-0744-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preoperative Mac‐2 binding protein glycosylation isomer level predicts postoperative ascites in patients with hepatic resection for hepatocellular carcinoma (2019)
  • Author(s): Ishii Norihiro、Harimoto Norifumi、Araki Kenichiro、Muranushi Ryo、Hoshino Kouki、Hagiwara Kei、Gantumur Dolgormaa、Yamanaka Takahiro、Tsukagoshi Mariko、Igarashi Takamichi、Tanaka Hiroshi、Watanabe Akira、Kubo Norio、Shirabe Ken
  • Journal Title: Hepatology Research Volume: 49 Issue: 12 Pages: 1398-1405
  • DOI: 10.1111/hepr.13412
  • Peer Reviewed
• [Journal Article] High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer (2019)
  • Author(s): Hagiwara Kei、Harimoto Norifumi、Yokobori Takehiko、Muranushi Ryo、Hoshino Kouki、Gantumur Dorgormaa、Yamanaka Takahiro、Ishii Norihiro、Tsukagoshi Mariko、Igarashi Takamichi、Tanaka Hiroshi、Watanabe Akira、Kubo Norio、Araki Kenichiro、Hosouchi Yasuo、Shirabe Ken
  • Journal Title: Annals of Surgical Oncology Volume: 27 Issue: 3 Pages: 924-930
  • DOI: 10.1245/s10434-019-07708-x
  • Peer Reviewed
• [Journal Article] Response to the letter by Dr. Naoya Yamada, and Dr. Koichi Mizuta regarding our manuscript: "Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis". (2019)
  • Author(s): Shirabe K, Bekki Y, Gantumur D, Araki K, Ishii N, Kuno A, Narimatsu H, Mizokami M.
  • Journal Title: J Gastroenterol Volume: 54 Issue: 2 Pages: 206-7
  • DOI: 10.1007/s00535-018-1524-5
  • Peer Reviewed / Open Access
• [Journal Article] Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis. (2018)
  • Author(s): Shirabe K, Bekki Y, Gantumur D, Araki K, Ishii N, Kuno A, Narimatsu H, Mizokami M.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 7 Pages: 819-826
  • DOI: 10.1007/s00535-017-1425-z
  • Peer Reviewed / Open Access
• [Presentation] 癌関連線維芽細胞が産生するサイトカインの制 御に基づく，肝癌の新たな治療戦略 (2020)
  • Author(s): 山中崇弘、播本憲史、村主遼、星野弘毅、萩原慶、 石井範洋、塚越真梨子、五十嵐隆通、渡辺亮、 久保憲生、新木健一郎、梅澤一夫、調憲
  • Organizer: 第120回日本外科学会