Functional analysis of deubiquitinating enzyme in bile cancer using zenograft model

• Project/Area Number: 16K19912
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Tohoku University
• Principal Investigator: Ishida Masaharu 東北大学, 大学病院, 助教 (90619660)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 胆嚢癌 / 遺伝子変異 / 脱ユビキチン化酵素 / 胆道癌 / BAP１ / 消化器外科 / 胆道外科 / クロマチンモデリング複合体 / クロマチンリモデリング複合体 / 外科 / 癌 / 遺伝子

Outline of Final Research Achievements

It was clarified in clinical surgery specimens that gene mutations of BAP1, which is a deubiquitinating enzyme, are frequently found in intrahepatic cholangiocarcinoma and gallbladder cancer. The gene mutation of BAP1 was associated with a decrease in BAP1 protein expression in cancer tissue, and cases with low expression of BAP1 gene showed a poor prognosis compared to high expression cases. Functional analysis of BAP1 was performed using a cancer cell lines, and it was shown that the decrease in BAP1 expression increases the cell migration ability and infiltration ability. On the other hand, there was no significant difference in proliferation ability.
Biliary tract cancers were cultured from clinical samples, and 3 lines have been established so far, and comprehensive analysis of genes was performed.

Academic Significance and Societal Importance of the Research Achievements

胆道癌、特に胆嚢癌や肝内胆管癌は、胆道癌のなかでも予後が特に不良であり、また日本人に多く認められるため、本邦における研究は特に重要である。
本研究は、脱ユビキチン化酵素であるBAP1が胆嚢癌において、海外の少数症例を対象とした研究に比べて、高頻度に変異していることを精度の高い方法で示し、またその変異が予後と関係していることを証明した。細胞株を用いた実験ではBAP1の発現低下が、癌の遊走能と浸潤能を増加させていることを示し、治療のターゲットとなり得ることを示した。

Research Products

• [Journal Article] Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. (2018)
  • Author(s): Hirosawa T1, Ishida M1, Ishii K1, Kanehara K1, Kudo K1, Ohnuma S1, Kamei T1, Motoi F1, Naitoh T1, Selaru FM2, Unno M1.
  • Journal Title: PLoS One. Volume: 13 Pages: 0206643-0206643
  • Peer Reviewed / Open Access / Int'l Joint Research