Glycan profiling relation to dedifferentiation of hepatocellular carcinoma with lectin microarray

• Project/Area Number: 17K16572
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Oita University
• Principal Investigator: Takayama Hiroomi 大分大学, 医学部, 客員研究員 (50733614)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝細胞癌 / レクチン / 糖鎖プロファイリング / 脱分化 / 糖転移酵素 / 高マンノース型糖鎖 / MGAT1 / 分化度

Outline of Final Research Achievements

We investigated glycosylation associated with the dedifferentiation of HCC within the same nodule, and glycosyltransferase related to the glycosylation.
We analyzed fifty HCC specimens using lectin microarray. Four lectins of NPA, Con A, GNA, and Calsepa were significantly elevated in moderately-differentiated components of HCC compared with well-differentiated components, and all lectins showed binding specificity to high-mannose glycans. Immunohistochemical staining of MGAT1, which is an essential glycosyltransferase that converts high-mannose glycans to complex- or hybrid-type N-glycans, showed significantly decreased expression in moderately-differentiated components. Low MGAT1 expression was associated with intrahepatic metastasis and had tendency for poor prognosis. Dedifferentiation of HCC is associated with an increase in high-mannose glycans, and MGAT1 may play a role in the dedifferentiation of HCC.

Academic Significance and Societal Importance of the Research Achievements

本研究では、同一腫瘍内で分化度の異なる成分を有する肝細胞癌について、発現する糖鎖変化を解析することで、脱分化に伴う糖鎖変化を明らかにした。高マンノース型糖鎖が脱分化に伴い増加していると考えられ、肝内転移や予後にも影響していることが示唆された。その糖鎖変化や関連する糖転移酵素の意義や機能解明までには至らなかったが、今後それらを明らかにすることで、脱分化メカニズムの解明や、脱分化制御による悪性化の制御、肝細胞癌の治療薬開発にも繋がると考えられた。

Research Products

• [Journal Article] Altered glycosylation associated with dedifferentiation of hepatocellular carcinoma: a lectin microarray-based study. (2020)
  • Author(s): Takayama H, Ohta M, Iwashita Y, Uchida H, Shitomi Y, Yada K, Inomata M
  • Journal Title: BMC cancer Volume: 20(3) Issue: 1
  • DOI: 10.1186/s12885-020-6699-5
  • Peer Reviewed / Open Access
• [Journal Article] Additional effects of duodenojejunal bypass on glucose metabolism in a rat model of sleeve gastrectomy. (2019)
  • Author(s): Takayama H, Ohta M, Tada K, Watanabe K, Kawasaki T, Endo Y, Iwashita Y, Inomata M.
  • Journal Title: Surg Today Volume: aheadofprint Issue: 7 Pages: 637-644
  • DOI: 10.1007/s00595-019-1772-x
  • Peer Reviewed
• [Journal Article] Laparoscopic liver resection in cirrhotic patients with specific reference to a difficulty scoring system. (2018)
  • Author(s): Uchida H, Iwashita Y, Tada K, Saga K, Takayama H, Hirashita T, Endo Y, Ohta M, Inomata M.
  • Journal Title: Langenbeck's Archives of Surgery Volume: 403(3) Issue: 3 Pages: 371-377
  • DOI: 10.1007/s00423-018-1671-4
  • Peer Reviewed
• [Journal Article] Secondary Unconjugated Bile Acids Induce Hepatic Stellate Cell Activation (2018)
  • Author(s): Saga Kunihiro、Iwashita Yukio、Hidano Shinya、Aso Yuiko、Isaka Kenji、Kido Yasutoshi、Tada Kazuhiro、Takayama Hiroomi、Masuda Takashi、Hirashita Teijiro、Endo Yuichi、Ohta Masayuki、Kobayashi Takashi、Inomata Masafumi
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 10 Pages: 3043-3043
  • DOI: 10.3390/ijms19103043
  • Peer Reviewed / Open Access
• [Presentation] 肝細胞癌の脱分化に関わる糖鎖の同定 レクチンマイクロアレイを用いた網羅的解析 (2018)
  • Author(s): 髙山洋臣，太田正之，岩下幸雄，内田博喜，多田和裕，嵯峨邦裕, 平下禎二郎, 遠藤裕一, 猪股雅史
  • Organizer: 日本外科学会
• [Presentation] 肝細胞癌の脱分化に関わる糖鎖の同定-レクチンマイクロアレイを用いた網羅的解析- (2018)
  • Author(s): 髙山 洋臣
  • Organizer: 日本外科学会