Role of miR-33 in tumorgenesis of medulloblastoma and anti-tumor immunity

• Project/Area Number: 19K09525
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kyoto University
• Principal Investigator: Mineharu Yohei 京都大学, 医学研究科, 特定准教授 (50716602)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: medulloblastoma / miR-33a / lipid metabolism / tumorgenecity / cancer / microRNA / tumorgenesis / 髄芽腫 / 脂質代謝 / miR-33 / mi-R33 / anti-tumor immunity

Outline of Research at the Start

小児において脳腫瘍は白血病に次いで多い悪性腫瘍で、髄芽腫は主要な組織型のひとつである。我々は過去の研究で、PD-L1の発現が髄芽腫の予後と逆相関することを報告した。本研究ではその分子機構の詳細解明を目指す。miR-33aに着目し、①miR-33aの抑制が髄芽腫発生に及ぼす影響、②髄芽腫の悪性度や免疫応答と関連するPD-L1、HMGA2やMYCとmiR-33aの相関関係、③miR-33aの抗腫瘍免疫反応性における役割、④免疫チェックポイント阻害薬（PD-1抗体/PD-L1抗体）とmiR-33aの併用効果について検証する。

Outline of Final Research Achievements

We showed that miR-33a depletion increase the penetrance of tumor formation in ptch1+/-medulloblastoma models. Specifically, around 30% of ptch1+/- mice develop medulloblastoma, while 80% of ptch1+/-; miR-33a-/- mice develop the tumor, indicating that miR-33a deletion increase the chance of developing medulloblastoma. Pathological findings suggest that the tumor was more invasive and we could find metastatic lesions. When the tumors were inoculated subcutaneously in nude mice, ptch1+/-; miR-33a-/- tumors form mass lesions more frequently than ptch1+/- tumors. Transcriptome analysis found scd1 was upregulated in miR-33a depleted tumors.

Academic Significance and Societal Importance of the Research Achievements

髄芽腫において、脂質代謝因子のmiR-33aを操作することで、腫瘍の発生や悪性度に影響を与えられることを明らかにした。miR-33は脂質代謝の他、c-Mycなどの増殖因子やPD-L1などの免疫分子にも影響することから、微小環境制御による腫瘍治療への応用が期待される。RNF213遺伝子も同様に脂質制御に関わっており、分子ネットワークを明らかにすることで、より正確な腫瘍制御につながる可能性がある。

Research Products

• [Journal Article] 髄芽腫と脂質代謝因子miR-33 (2020)
  • Author(s): 峰晴陽平
  • Journal Title: Medical Science Digest Volume: 46 Pages: 488-489
• [Presentation] 脂質代謝因子miR-33aは髄芽腫の発生と浸潤を制御する (2021)
  • Author(s): 峰晴陽平、松井恭澄、尾市雄輝、鎌田貴彦、森本貴昭、丹治正大、中尾哲史、堀江貴裕、荒川芳輝、宮本享
  • Organizer: 日本脳腫瘍学会
• [Presentation] 脂質制御因子miR-33a欠損は髄芽腫の発生と転移を促進する (2021)
  • Author(s): 峰晴陽平、松井恭澄、鎌田貴彦、尾市雄輝、寺田行範、森本貴昭、藤原敏孝、丹治正大、荒川芳輝、宮本享
  • Organizer: 脳腫瘍病理学会
• [Presentation] Significance of RNF213 in tumorgenicity of medulloblastoma. (2020)
  • Author(s): Mineharu Y, Oichi Y, Kamata T, Matsui Y, Morimoto T, Tanji M, Kobayashi H, Okuda H, Harada KH, Koizumi A, Arakawa Y and Miyamoto S.
  • Organizer: International Symposium on Pediatric Neuro-Oncology
  • Int'l Joint Research
• [Presentation] Significance of miR-33 in generation and progression of medulloblastoma. (2020)
  • Author(s): Matsui Y, Mineharu Y, Oichi Y, Kamata T, Morimoto T, Tanji M, Nakao T, Horie T, Ono K, Arakawa Y and Miyamoto S.
  • Organizer: International Symposium on Pediatric Neuro-Oncology
  • Int'l Joint Research
• [Presentation] Significance of mi-R33 in generation and progression of medulloblastoma (2020)
  • Author(s): Yasuzumi Matsui, Yohei Mineharu, Takaaki Morimoto, Yuki Oichi, Takahiko Kamata, Masahiro Tanji, Testushi Nakao, Takahiro Horie, Koh Ono, Yoshiki Arakawa and Susumu Miyamoto
  • Organizer: 19th International Symposium of Pediatric Neuro-Oncology
  • Int'l Joint Research
• [Presentation] Significance of RNF213 in tumorgenicity of medulloblastoma (2020)
  • Author(s): Yohei Mineharu, Yuki Oichi, Takahiko Kamata, Yasuzumi Matsui, Takaaki Morimoto, Masahiro Tanji, Hatasu Kobayashi, Hiroko Okuda, Kouji H Harada, Akio Koizumi, Yoshiki Arakawa and Susumu Miyamoto
  • Organizer: 19th International Symposium of Pediatric Neuro-Oncology
  • Int'l Joint Research