Establishment of treatment strategy for esophageal cancer targeting mitochondrial dysfunction

• Project/Area Number: 17K16550
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: Tanaka Koji 大阪大学, 医学部附属病院, 助教 (70621019)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 食道癌 / ミトコンドリアDNA / mtDNA / 癌幹細胞 / ミトコンドリア / 治療抵抗性

Outline of Final Research Achievements

We measured mtDNA copy number in resected specimens of esophageal squamous cell carcinoma that underwent radical surgery after preoperative treatment. The histopathological effects of chemotherapy were significantly poor in the mtDNA copy number low group. Mitochondrial transcription factor A (TFAM) was knocked down (KD) with shRNA to establish a mtDNA copy number reduced cell line (TE8: approximately 40%, TE11: approximately 60%). Comparison of anticancer drug sensitivities showed that cells with reduced mtDNA copy number had reduced anticancer drug sensitivity. Similar results were also confirmed in the subcutaneous tumor model.
From the above results, it was confirmed that mtDNA copy number-reduced cells are resistant to treatment with anti-cancer agents.

Academic Significance and Societal Importance of the Research Achievements

本研究結果は、化学療法の治療抵抗性にmtDNAコピー数減少が関与することを示唆している。すなはち、何らかの理由で減少しているmtDNAコピー数を増加させることができれば化学療法の効果が改善し、ひいては食道癌の治療成績向上につながると考えられる。これまで、mtDNAと化学療法抵抗性に言及した報告はほとんどなく、新たな治療戦略につながる可能性がある。

Research Products

• [Journal Article] Esophageal squamous cell carcinoma with low mitochondrial copy number has mesenchymal and stem-like characteristics, and contributes to poor prognosis (2018)
  • Author(s): Masuike Yasunori、Tanaka Koji、Makino Tomoki、Yamasaki Makoto、Miyazaki Yasuhiro、Takahashi Tsuyoshi、Kurokawa Yukinori、Nakajima Kiyokazu、Mori Masaki、Doki Yuichiro
  • Journal Title: PLOS ONE Volume: 13 Issue: 2 Pages: e0193159-e0193159
  • DOI: 10.1371/journal.pone.0193159
  • Peer Reviewed / Open Access
• [Presentation] Low mitochondrial copy number induces resistance to chemotherapy in esophageal cancer (2018)
  • Author(s): Koji Tanaka
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Low copy number of mtDNA is associated with cancer stemness in ESCC (2018)
  • Author(s): Takeo Hara
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Low copy number of mtDNA is associated with cancer stemness in ESCC (2018)
  • Author(s): T. Hara, Y. Masuike, K. Tanaka, T. Makino, M. Yamasaki, Y. Miyazaki, T. Takahashi, Y. Kurokawa, H. Eguchi, K. Nakajima, M. Mori, Y. Doki;
  • Organizer: AACR
  • Int'l Joint Research