Molecular functions of pancreatic oncogenesis induced by dysregulation of ubiquitin ligases.

• Project/Area Number: 21H02893
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kishikawa Takahiro 東京大学, 医学部附属病院, 助教 (00724171)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2023: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2022: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 膵癌 / ユビキチン化 / マウスモデル / ユビキチン化酵素 / 翻訳後修飾

Outline of Research at the Start

細胞内で生成されたタンパク質は、種々の修飾を受けてその安定性や機能を変化させることによって複雑な生命活動を維持しています。その代表的存在であるユビキチン修飾系は予想以上に多彩な機能を標的タンパク質に付加すること、また疾患の発生にも密接に関わっていることが分かってきました。本研究では、種々の癌で異常が報告されているユビキチン化酵素に着目して、膵癌における発癌促進機能の機序解明とその制御法の開発を目的として研究を遂行していきます。

Outline of Final Research Achievements

This study aimed to elucidate the biological roles of WWP1, an E3 ubiquitin ligase which is involved in the development and progression of various cancers. In the genetically engineered mouse model with specific overexpression of WWP1 in the pancreatic tissue, tumorigenesis originating from acinar cells was significantly accelerated when combining with mutant KRAS expression. Furthermore, WWP1 inhibition suppressed tumor growth in pancreatic cancer cell lines, highlighting therapeutic potential of targeting WWP1.

Academic Significance and Societal Importance of the Research Achievements

複数の癌種において発現が亢進しているWWP1の発癌促進機能について、今まで報告のない膵癌において、遺伝子改変マウスモデルを用いて解析した点に新規性があると考える。その分子機序についてさらなる解析を進めることで、ユビキチン関連酵素が発癌に積極的に関与する病態モデルの提唱することが可能となるかもしれない。また、WWP1阻害による膵癌細胞の増殖抑制効果についても、その分子機序を含めて検討を行ったことで、WWP1が難治癌である膵癌の新規治療ターゲットとなり得る可能性を見出すことできた。

Research Products

• [Journal Article] Satellite double-stranded RNA induces mesenchymal transition in pancreatic cancer by regulating alternative splicing (2024)
  • Author(s): Iwata Takuma、Kishikawa Takahiro、Seimiya Takahiro、Notoya Genso、Suzuki Tatsunori、Shibata Chikako、Miyakawa Yu、Odawara Nariaki、Funato Kazuyoshi、Tanaka Eri、Yamagami Mari、Sekiba Kazuma、Otsuka Motoyuki、Koike Kazuhiko、Fujishiro Mitsuhiro
  • Journal Title: Journal of Biological Chemistry Volume: 300 Issue: 3 Pages: 105742-105742
  • DOI: 10.1016/j.jbc.2024.105742
  • Peer Reviewed / Open Access
• [Journal Article] Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells (2024)
  • Author(s): Miyakawa Yu、Otsuka Motoyuki、Shibata Chikako、Seimiya Takahiro、Yamamoto Keisuke、Ishibashi Rei、Kishikawa Takahiro、Tanaka Eri、Isagawa Takayuki、Takeda Norihiko、Kamio Noriaki、Imai Kenichi、Fujishiro Mitsuhiro
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 17 Issue: 5 Pages: 745-767
  • DOI: 10.1016/j.jcmgh.2024.01.010
  • Peer Reviewed / Open Access
• [Journal Article] Increased expression of TNFRSF14 and LIGHT in biliary epithelial cells of patients with primary sclerosing cholangitis (2024)
  • Author(s): Kanai S, Fujiwara H, Mizuno S, Kishikawa T, Nakatsuka T, Hamada T, Tanaka M, Arita J, Nakai Y, Isayama H, Kasuga M, Tateishi R, Tateishi K, Ushiku T, Hasegawa K, Koike K, Fujishiro M.
  • Journal Title: Dig Liver Dis . Volume: 56(2) Issue: 2 Pages: 305-311
  • DOI: 10.1016/j.dld.2023.08.057
  • Peer Reviewed / Open Access
• [Journal Article] Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA (2023)
  • Author(s): Funato Kazuyoshi、Miyake Nozomi、Sekiba Kazuma、Miyakawa Yu、Seimiya Takahiro、Shibata Chikako、Kishikawa Takahiro、Otsuka Motoyuki
  • Journal Title: Hepatology Communications Volume: 7 Issue: 11
  • DOI: 10.1097/hc9.0000000000000313
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicle mediated RNA editing may underlie the heterogeneity and spread of hepatocellular carcinoma in human tissue and in vitro (2023)
  • Author(s): Shibata Chikako、Otsuka Motoyuki、Shimizu Takayuki、Seimiya Takahiro、Kishikawa Takahiro、Aoki Taku、Fujishiro Mitsuhiro
  • Journal Title: Oncology Reports Volume: 50 Issue: 5 Pages: 194-194
  • DOI: 10.3892/or.2023.8631
  • Peer Reviewed / Open Access
• [Journal Article] Combination of serum human satellite RNA and miR-21-5p levels as a biomarker for pancreatic cancer (2023)
  • Author(s): Seimiya Takahiro、Suzuki Tatsunori、Iwata Takuma、Kishikawa Takahiro、Sekiba Kazuma、Shibata Chikako、Ishigaki Kazunaga、Fujiwara Hiroaki、Oyama Hiroki、Kanai Sachiko、Sato Tatsuya、Nakai Yousuke、Ishibashi Rei、Moriyama Masaru、Nakagawa Ryo、Ijichi Hideaki、Otsuka Motoyuki、Koike Kazuhiko
  • Journal Title: iScience Volume: 26 Issue: 2 Pages: 106021-106021
  • DOI: 10.1016/j.isci.2023.106021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HNF1B‐driven three‐dimensional chromatin structure for molecular classification in pancreatic cancers (2022)
  • Author(s): Kato Hiroyuki、Tateishi Keisuke、Iwadate Dosuke、Yamamoto Keisuke、Fujiwara Hiroaki、Nakatsuka Takuma、Kudo Yotaro、Hayakawa Yoku、Ijichi Hideaki、Otsuka Motoyuki、Kishikawa Takahiro、Takahashi Ryota、Miyabayashi Koji、Nakai Yousuke、Hirata Yoshihiro、Toyoda Atsushi、Morishita Shinichi、Fujishiro Mitsuhiro
  • Journal Title: Cancer Science Volume: 114 Issue: 4 Pages: 1672-1685
  • DOI: 10.1111/cas.15690
  • Peer Reviewed / Open Access
• [Journal Article] Smaller extracellular vesicles are released from pancreatic cancer cells by the alteration of the lipid composition under low glucose conditions (2022)
  • Author(s): Shibata Chikako、Otsuka Motoyuki、Seimiya Takahiro、Ishigaki Kazunaga、Miyakawa Yu、Kishikawa Takahiro、Fujishiro Mitsuhiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 637 Pages: 314-321
  • DOI: 10.1016/j.bbrc.2022.11.040
  • Peer Reviewed / Open Access
• [Journal Article] Lipolysis by pancreatic cancer‐derived extracellular vesicles in cancer‐associated cachexia via specific integrins (2022)
  • Author(s): Shibata Chikako、Otsuka Motoyuki、Seimiya Takahiro、Kishikawa Takahiro、Ishigaki Kazunaga、Fujishiro Mitsuhiro
  • Journal Title: Clinical and Translational Medicine Volume: 12 Issue: 11 Pages: 1089-1089
  • DOI: 10.1002/ctm2.1089
  • Peer Reviewed / Open Access
• [Journal Article] WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models (2021)
  • Author(s): Kishikawa Takahiro、Higuchi Hiroshi、Wang Limei、Panch Nivedita、Maymi Valerie、Best Sachem、Lee Samuel、Notoya Genso、Toker Alex、Matesic Lydia E.、Wulf Gerburg M.、Wei Wenyi、Otsuka Motoyuki、Koike Kazuhiko、Clohessy John G.、Lee Yu-Ru、Pandolfi Pier Paolo
  • Journal Title: Journal of Clinical Investigation Volume: 131 Issue: 24
  • DOI: 10.1172/jci140436
  • Peer Reviewed / Open Access
• [Journal Article] Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells. (2021)
  • Author(s): Suzuki T, Kishikawa T, Sato T, Takeda N, Sugiura Y, Seimiya T, Sekiba K, Ohno M, Iwata T, Ishibashi R, Otsuka M, Koike K.
  • Journal Title: Cancer Gene Ther. Volume: - Issue: 5 Pages: 505-518
  • DOI: 10.1038/s41417-021-00326-4
  • Peer Reviewed / Open Access
• [Presentation] 1.Double-stranded RNA derived from tandem repeat sequences induces mesenchymal transition in pancreatic cancer cells by regulating alternative splicing. (2023)
  • Author(s): Takahiro Kishikawa, Takuma Iwata, Takahiro Seimiya, Genso Notoya, Tatsunori Suzuki, Chikako Shibata, Kazuhiko Koike, Motoyuki Otsuka, and Mitsuhiro Fujishiro
  • Organizer: AACR Special Conference in Cancer Research: Pancreatic Cancer
  • Int'l Joint Research
• [Remarks] 東京大学医学部消化器内科 基礎研究チーム(岸川グループ)
  • URL: https://sites.google.com/site/225kenncrna/home