The study of novel diagnosis and treatment for endometrial cancer targeting aberrant DNA methylation

• Project/Area Number: 16K11154
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Keio University
• Principal Investigator: Banno Kouji 慶應義塾大学, 医学部(信濃町), 准教授 (70265875)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 子宮内膜癌 / 異常メチル化 / miR-663a / メトホルミン / 子宮体癌 / EDN2 / ジエノゲスト / リンチ症候群 / MMR遺伝子 / エピミューテーション / エピゲノム / メチル化

Outline of Final Research Achievements

(1) Based on genome-wide bisulfite sequencing, peripheral blood cells(PBCs) DNA in M-H cases had significant hypermethylation in the miR-663a promoter region, compared to U cases (meth. Diff. > 25%, q-value < 0.01). Consistent with this methylation status, miR-663a expression was lower in M-H PBCs than in U PBCs. DNMTs expression levels in M-H endometrial cancer were higher than those in U endometrial cancer.
(2) Metformin had a dose-dependent anticancer effect on endometrial cancer cell lines. Moreover, the combined treatment also caused lower cell viability.The microarray analysis indicated that EDN2 expression was upregulated in cells subject to the combined treatment. EDN2 expression was upregulated in each cell line upon treatment with a demethylating agent.

Academic Significance and Societal Importance of the Research Achievements

（１）腫瘍部において異常高メチル化を認める子宮内膜癌患者は、正常細胞においても一部の遺伝子に異常メチル化を認めた。正常細胞における異常メチル化が癌のフェノタイプに寄与する可能性が示唆された。今後、癌の予防や早期発見に繋がる結果と考えられる。
（２）本研究において抗癌剤としての有用性を検討した薬剤は、既に他の疾病に対し処方されているため、安全性や副作用の情報が蓄積されている。新規の抗癌剤開発にかかる時間短縮・費用削減など、臨床応用されれば意義は大きいと考えられる。

Research Products

• [Journal Article] Genome-wide DNA methylation sequencing revealed that miR-663a is a novel epimutation candidate in CIMP- high endometrial cancer. (2017)
  • Author(s): Megumi Yanokura, Kouji Banno, Masataka Adachi, Daisuke Aoki, Kuniya Abe
  • Journal Title: International Journal of Oncology Volume: - Issue: 6 Pages: 1934-1946
  • DOI: 10.3892/ijo.2017.3966
  • Peer Reviewed / Open Access
• [Journal Article] Carcinoma of the lower uterine segment diagnosed with Lynch syndrome based on MSH6 germline mutation: A case report. (2017)
  • Author(s): Adachi M, Banno K, Masuda K, Yanokura M, Iijima M, Takeda T, Kunitomi H, Kobayashi Y, Yamagami W, Hirasawa A, Kameyama K, Sugano K, Aoki D.
  • Journal Title: J Obstet Gynaecol Res Volume: 43(2) Issue: 2 Pages: 416-420
  • DOI: 10.1111/jog.13202
  • Peer Reviewed / Open Access