Analysis of stromal cell reprogramming induced by cancer stem cells

• Project/Area Number: 21H02900
• 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: Kanazawa University
• Principal Investigator: YAMASHITA TARO 金沢大学, 医学系, 教授 (90377432)
• 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: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2022: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2021: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 癌幹細胞 / 遠隔転移 / 上皮間葉転換 / 肝癌

Outline of Research at the Start

癌幹細胞は浸潤先端で間質細胞に接して存在し、癌幹細胞によりリプログラミングを受
けた間質細胞では血管新生や線維化、免疫チェックポイントなど、癌治療における重要な標
的分子が発現する。本研究は代表的な難治癌である肝細胞癌に着目し、上皮系、間葉系の異
なる癌幹細胞が間質細胞のリプログラミングに与える影響を１細胞レベルで網羅的に解明し、間質細胞を標的とした難治性肝癌に対する新たな診断治療標的分子の導出を目指す。

Outline of Final Research Achievements

We previously demonstrated that two distinct cancer stem cells, namely EpCAM-positive epithelial cancer stem cells and CD90-positive mesenchymal cancer stem cells, exit in human hepatocellular carcinoma. Especially, CD90-positive cancer stem cells play a fundamental role on distant organ metastasis of hepatocellular carcinoma. Here we evaluated the role of cancer associated fibroblasts on EpCAM-positive epithelial cancer stem cells. We found that the presence of cancer associated fibroblasts activated the JUNB transcription factor to induce CD90-positive mesenchymal cancer stem cells, resulted in the acquisition of metastatic capacity of EpCAM-positive epithelial cancer stem cells. Thus, our study demonstrated the novel role of JUNB on epithelial-mesenchymal transition and cancer metastasis, suggested that JUNB might be a good molecular target to prevent HCC metastasis.

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌の遠隔転移は患者の予後不良につながる一方、遠隔転移プログラムを阻害する治療薬はない。我々はCD90陽性癌幹細胞が遠隔転移を起こし、その血清マーカーとしてLG2mを同定したが、治療薬候補はまだ開発できていない。本研究では上皮系癌幹細胞から間葉系癌幹細胞が出現する機序として癌関連線維芽細胞の役割を同定、その機序として腫瘍辺縁部におけるJUNBの活性化を見出し、JUNB過剰発現が遠隔転移を起こすことを同定した。本研究成果から、JUNBを標的にした薬物候補の開発が肝細胞癌の遠隔転移阻害剤として有望な可能性が示唆され、新たな癌分子標的の創出に至ったと考える。

Research Products

• [Journal Article] BMP9-ID1 Pathway Attenuates N6-Methyladenosine Levels of CyclinD1 to Promote Cell Proliferation in Hepatocellular Carcinoma (2024)
  • Author(s): Han Chen, Mingming Zhang, Jianhao Li, Miao Liu, Dan Cao, Ying-Yi Li, Taro Yamashita, Kouki Nio, Hong Tang
  • Journal Title: Int J Mol Sci . Volume: 25 Issue: 2 Pages: 1-21
  • DOI: 10.3390/ijms25020981
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Beta-Hydroxyisovaleryl-Shikonin Eradicates Epithelial Cell Adhesion Molecule-Positive Liver Cancer Stem Cells by Suppressing dUTP Pyrophosphatase Expression (2023)
  • Author(s): Yoshiro Asahina 1, Hajime Takatori 1, Kouki Nio 1, Hikari Okada 1, Takehiro Hayashi 1, Tomoyuki Hayashi 1, Tomomi Hashiba 1, Tsuyoshi Suda 1, Masaki Nishitani 1, Saiho Sugimoto 1, Masao Honda 1, Shuichi Kaneko 1, Taro Yamashita 1
  • Journal Title: Int J Mol Sci . Volume: 24 Issue: 22 Pages: 1-11
  • DOI: 10.3390/ijms242216283
  • Peer Reviewed / Open Access
• [Journal Article] Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis (2023)
  • Author(s): Matsuda Y, Ye J, Yamakawa K, Mukai Y, Azuma K, Wu L, Masutomi K, Yamashita T, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Kojima M, Kaneko S, Haba R, Kontani K, Kanaji N, Okano K, Muto-Ishizuka M, Yokohira M, Saoo K, Imaida K, Suizu F.
  • Journal Title: J Natl Cancer Inst . Volume: 115 Issue: 2 Pages: 208-218
  • DOI: 10.1093/jnci/djac226
  • Peer Reviewed / Open Access
• [Journal Article] FOXM1 Is a Novel Molecular Target of AFP-Positive Hepatocellular Carcinoma Abrogated by Proteasome Inhibition (2022)
  • Author(s): Li Ru、Okada Hikari、Yamashita Taro、Nio Kouki、Chen Han、Li Yingyi、Shimakami Tetsuro、Takatori Hajime、Arai Kuniaki、Sakai Yoshio、Yamashita Tatsuya、Mizukoshi Eishiro、Honda Masao、Kaneko Shuichi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 15 Pages: 8305-8305
  • DOI: 10.3390/ijms23158305
  • Peer Reviewed / Open Access
• [Journal Article] BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma (2022)
  • Author(s): Chen Han、Nio Kouki、Tang Hong、Yamashita Taro、Okada Hikari、Li Yingyi、Doan Phuong Thi Bich、Li Ru、Lv Junyan、Sakai Yoshio、Yamashita Tatsuya、Mizukoshi Eishiro、Honda Masao、Kaneko Shuichi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 3 Pages: 1475-1475
  • DOI: 10.3390/ijms23031475
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs (2022)
  • Author(s): Matsuda Y, Yamashita T, Ye J, Yasukawa M, Yamakawa K, Mukai Y, Machitani M, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Yamada S, Takei J, Kaneko MK, Kojima M, Kaneko S, Masaki T, Hirata M, Haba R, Kontani K, Kanaji N, Miyatake N, Okano K, Kato Y, Masutomi K
  • Journal Title: J Pathol Volume: 257 Issue: 2 Pages: 172-185
  • DOI: 10.1002/path.5876
  • Peer Reviewed / Open Access
• [Journal Article] Dickkopf-1 Promotes Angiogenesis and is a Biomarker for Hepatic Stem Cell-like Hepatocellular Carcinoma. (2021)
  • Author(s): Suda T, Yamashita T, Sunagozaka H, Okada H, Nio K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: Int J Mol Sci Volume: 23 Issue: 5 Pages: 1-17
  • DOI: 10.3390/ijms23052801
  • Peer Reviewed / Open Access
• [Journal Article] Liver cancer stem cells: Recent progress in basic and clinical research. (2021)
  • Author(s): Yamashita T, Kaneko S.
  • Journal Title: Regen Ther. Volume: 17 Pages: 34-37
  • DOI: 10.1016/j.reth.2021.03.002
  • Peer Reviewed / Open Access
• [Journal Article] Serum laminin γ2 monomer as a novel diagnostic and predictive biomarker for hepatocellular carcinoma. (2021)
  • Author(s): T Yamashita, N Koshikawa, T Shimakami, T Terashima, M Nakagawa, K Nio, R Horii, N Iida, K Kawaguchi, K Arai, Y Sakai, T Yamashita, E Mizukoshi, M Honda, A Kitao, S Kobayashi, S Takahara, Y Imai, K Yoshimura, T Murayama, Y Nakamoto, E Yoshida, T Yoshimura, M Seiki, S Kaneko.
  • Journal Title: Hepatology Volume: - Issue: 2 Pages: 760-775
  • DOI: 10.1002/hep.31758
  • Peer Reviewed / Open Access
• [Presentation] 新たな肝がん腫瘍マーカー、ラミニンγ2単鎖の有用性 (2023)
  • Author(s): 山下太郎
  • Organizer: 日本消化器病学会北陸支部第48回教育講演会
  • Invited
• [Presentation] 肝炎・肝がんにおけるラミニンγ2単鎖発言の意義 (2023)
  • Author(s): 山下太郎
  • Organizer: 日本消化器病学会関東支部第374回例会／特別講演
  • Invited
• [Presentation] 新たな肝がん腫瘍マーカー、ラミニンγ2単鎖測定の意義 (2023)
  • Author(s): 山下太郎
  • Organizer: 第88回日本消化器病学会北陸支部生涯教育講演会
  • Invited
• [Presentation] AFP陽性肝細胞癌に高発現するFOXM1を標的とした プロテアソーム阻害剤Carfilzomibの治療効果検討 (2022)
  • Author(s): 丹尾幸樹、山下太郎、金子周一
  • Organizer: 日本消化器病学会総会
• [Presentation] 5.Recent progress in basic and clinical research of liver cancer stem cells: correlation of liver cancer stem cells with molecular hepatocellular carcinoma subclasses (2021)
  • Author(s): 山下太郎
  • Organizer: 7th Asian Conference on Tumor Ablation
  • Int'l Joint Research / Invited
• [Presentation] Recent progress in basic and clinical research of liver cancer stem cells (2021)
  • Author(s): 山下太郎
  • Organizer: APASL Oncology 2021
  • Int'l Joint Research / Invited