Molecular Basis of Intrahepatic Cholangiocarcinoma Caused by Epigenomic Abnormalities

• Project/Area Number: 20K08353
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hakuta Ryunosuke 東京大学, 医学部附属病院, 助教 (10843716)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 届出研究員 (20396948)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 胆管癌 / 肝内胆管癌 / 膵癌

Outline of Research at the Start

肝内胆管癌（ICC）は難治癌であり、その起源や発癌経路については不明な点が多い。ICCにおける遺伝子変異と生物学的特性の関連についての報告は少なく、有効な分子標的も殆どない。ICCにおいて変異が認められるIDH1遺伝子が、悪性度や膵癌同様の豊富な腫瘍間質形成に及ぼす影響などについては全く分かっていない。既に作成した肝内胆管癌発生マウスモデルを用いて、IDH1遺伝子異常が悪性度あるいは腫瘍間質形成に及ぼす影響を検討する。得られた知見はヒト肝内胆管癌組織検体においても検証する。ICCにおける豊富な間質についてもエピゲノム制御阻害が抑制効果を持つどうか検討する。

Outline of Final Research Achievements

Using a mouse model of intrahepatic cholangiocarcinogenesis, we examined the effects of epigenome-related gene aberrations on malignancy or tumor stroma formation, and the possibility that inhibition of chromatin regulation may also have inhibitory effects on abundant stroma in ICCs. We generated genetically engineered mice capable of inducing tissue-specific expression of wild-type IDH1 or mutant IDH1 (R132C); CAG-LSL-IDH1WT Tg and CAG-LSLIDH1(R132C mutant) Tg. We have confirmed expression of the transgenic IDH1 gene in the liver and production of 2-HG specific to the mutant mice by crossing them with Alb-Cre mice. These were crossed with other transgenic mice and analyzed.

Academic Significance and Societal Importance of the Research Achievements

ICCで変異が認められるエピゲノム関連遺伝子が、その悪性度や豊富な腫瘍間質形成に及ぼす影響については全く不明であり、同時にクロマチン修飾制御との関連も解明されていない。最近ではそれら遺伝子異常がICCにおいても癌細胞のみならず腫瘍間質に作用している可能性が考えられ、同時にクロマチン修飾との関連も推察されるが、その分子機序を解明した報告はない。さらに遺伝子異常の標的化が間質細胞や免疫反応を介した抗腫瘍戦略として有効である可能性も想起される。本研究はエピゲノム異常がもたらす肝内胆管癌の高悪性度形質の分子基盤を明らかにする学術的意義を有する。

Research Products

• [Journal Article] Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study (2023)
  • Author(s): Suzuki Yukari、Saito Kei、Nakai Yousuke、Oyama Hiroki、Kanai Sachiko、Suzuki Tatsunori、Sato Tatsuya、Hakuta Ryunosuke、Ishigaki Kazunaga、Saito Tomotaka、Hamada Tsuyoshi、Takahara Naminatsu、Tateishi Ryosuke、Fujishiro Mitsuhiro
  • Journal Title: Supportive Care in Cancer Volume: 31 Issue: 3
  • DOI: 10.1007/s00520-023-07659-w
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct (2023)
  • Author(s): Hamada Tsuyoshi、Oyama Hiroki、Nakai Yousuke、Tateishi Keisuke、Ushiku Tetsuo、Hasegawa Kiyoshi、Fujishiro Mitsuhiro
  • Journal Title: Clinical Gastroenterology and Hepatology Volume: - Issue: 7 Pages: 1792-1801.e3
  • DOI: 10.1016/j.cgh.2023.01.032
  • Peer Reviewed / Open Access
• [Journal Article] Increased risk of biliary infection after biliary stent placement in users of proton pump inhibitors (2022)
  • Author(s): Hakuta Ryunosuke、Nakai Yousuke、Oyama Hiroki、Noguchi Kensaku、Kanai Sachiko、Nomura Yusuke、Suzuki Tatsunori、Ishigaki Kazunaga、Saito Kei、Saito Tomotaka、Hamada Tsuyoshi、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Moriya Kyoji、Fujishiro Mitsuhiro
  • Journal Title: DEN Open Volume: 3 Issue: 1
  • DOI: 10.1002/deo2.129
  • Peer Reviewed
• [Journal Article] MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages (2022)
  • Author(s): Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, et al.
  • Journal Title: Gastroenterology Volume: 162 Issue: 4 Pages: 1272-1287
  • DOI: 10.1053/j.gastro.2021.12.254
  • Peer Reviewed / Open Access