Analysis of molecular bases of the relationship between mesenchymal phenotype and metabolic reprogram in clear cell renal cancer

• Project/Area Number: 17K07151
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka University
• Principal Investigator: Hashimoto Shigeru 大阪大学, 免疫学フロンティア研究センター, 寄附研究部門准教授 (50311303)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Arf6 / EZH2 / 翻訳制御 / エピジェネティクス / 腎明細胞癌 / 活性酸素種 / ミトコンドリア / オートファジー / 腎癌 / EMT / 癌 / 発現制御 / シグナル伝達

Outline of Final Research Achievements

We have previously shown that the Arf6 pathway is involved in the acquisition of invasiveness and drug-resistance of breast, renal, and pancreatic cancer. In this project, we demonstrated that the epigenetic regulator, EZH2, which has been reported to be statistically significantly associated with the poor prognosis of clear cell renal cell carcinoma (ccRCC), post-transcriptionally augments the protein expression levels of compounds of Arf6 pathway. Moreover, we found that Arf6 pathway is involved in the suppression of the amount of intracellular reactive oxygen species in ccRCC via activation of autophagy/mitophagy.

Academic Significance and Societal Importance of the Research Achievements

本研究により、これまで不明であった腎明細胞癌におけるEZH2と予後不良との相関に関し、EZH2を介したArf6経路の発現誘導により浸潤・転移性、薬剤耐性が惹起される作用機序を示した。さらに、腎明細胞癌の多くはVHL遺伝子変異のため偽低酸素状態であり活性酸素種の抑制が必須であるが、Arf6経路が活性酸素種を除去することにより代謝リプログラムに関与することが示唆された。本研究成果により、これまで有効な抗癌剤治療が無かった悪性腎明細胞癌に対して、Arf6経路を構成する分子群並びにその制御に関わる分子群を分子標的とした効果的・効率的な診断・治療戦略の創出に寄与することが期待される。

Research Products

• [Journal Article] 1.High expression of AMAP1, an ARF6 effector, is associated with elevated levels of PD¬L1 and fibrosis of pancreatic cancer (2020)
  • Author(s): Tsutaho A, Hashimoto A, Hashimoto S, Hata S, Kachi S, Hirano S, and Sabe H.
  • Journal Title: Cell Communication and Signaling Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production (2020)
  • Author(s): Metwally Hozaifa、Tanaka Toshio、Li Songling、Parajuli Gyanu、Kang Sujin、Hanieh Hamza、Hashimoto Shigeru、Chalise Jaya P.、Gemechu Yohannes、Standley Daron M.、Kishimoto Tadamitsu
  • Journal Title: Science Signaling Volume: 13 Issue: 624 Pages: 624-624
  • DOI: 10.1126/scisignal.aay0574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics and immune evasion of pancreatic cancer (2019)
  • Author(s): Hashimoto, S*., Furukawa, S*., Hashimoto, A*., Tsutaho, A., Fukao, A., Sakamura, Y., Parajuli, G., Onodera, Y., Otsuka, Y., Handa, H., Oikawa, T., Hata, S., Nishikawa Y., Mizukami, Y., Kodama, Y., Murakami M., Fujiwara, T., Hirano, S., and Sabe, H. (*Equally contributed)
  • Journal Title: Proceedings of the National Academy of the Sciences of the United States of America Volume: 116 Issue: 35 Pages: 17450-17459
  • DOI: 10.1073/pnas.1901765116
  • Peer Reviewed / Open Access
• [Journal Article] Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis (2019)
  • Author(s): Chalise Jaya Prakash、Hashimoto Shigeru、Parajuli Gyanu、Kang Sujin、Singh Shailendra Kumar、Gemechu Yohannes、Metwally Hozaifa、Nyati Kishan Kumar、Dubey Praveen Kumar、Zaman Mohammad Mahabub-Uz、Nagahama Yasuharu、Hamza Hanieh、Masuda Kazuya、Kishimoto Tadamitsu
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 30 Pages: 15128-15133
  • DOI: 10.1073/pnas.1906712116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endothelin type B receptor interacts with the 78-kDa glucose-regulated protein. (2019)
  • Author(s): Mazaki, Y., Higashi, T., Onodera, Y., Nam, JM., Hashimoto, A., Hashimoto, S., Horinouchi, T., and Miwa, S.
  • Journal Title: FEBS Lett Volume: 593(6) Issue: 6 Pages: 644-651
  • DOI: 10.1002/1873-3468.13347
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epithelial-specific histone modification of the miR-96/182 locus targeting AMAP1 mRNA predisposes p53 to suppress cell invasion in epithelial cells. (2018)
  • Author(s): Handa, H*., Hashimoto, A*., Hashimoto S., Sugino, S., Oikawa, T., and Sabe, H.
  • Journal Title: Cell Commun. Signal. Volume: 16(1) Issue: 1 Pages: 94-94
  • DOI: 10.1186/s12964-018-0302-6
  • NAID: 120006585787
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs. (2018)
  • Author(s): Gemechu Y, Millrine D, Hashimoto S, Prakash J, Sanchenkova K, Metwally H, Gyanu P, Kang S, Kishimoto T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 115(46) Issue: 46 Pages: 11802-11807
  • DOI: 10.1073/pnas.1814446115
  • Peer Reviewed / Open Access
• [Journal Article] Necessity of p53-binding to the CDH1 locus for its expression defines two epithelial cell types differing in their integrity (2018)
  • Author(s): Oikawa T, Otsuka Y, Onodera Y, Horikawa M, Handa H, Hashimoto S, Suzuki Y and Sabe H
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1595-1595
  • DOI: 10.1038/s41598-018-20043-7
  • NAID: 120006414006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent overexpression of AMAP1, an Arf6 effector in cell invasion, is characteristic of the MMTV-PyMT rather than the MMTV-Neu human breast cancer model (2018)
  • Author(s): Otsuka Y, Oikawa T, Yoshino H, Hashimoto S, Handa H, Yamamoto H, Hashimoto A, and Sabe H.
  • Journal Title: Cell Commun Signal Volume: 16(1) Issue: 1 Pages: 1-9
  • DOI: 10.1186/s12964-017-0212-z
  • NAID: 120006410532
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic significance of erythrocyte protein band 4.1-like5 expression in upper urinary tract urothelial carcinoma (2017)
  • Author(s): Daimon T, Kosaka T, Kikuchi E, Mikami S, Miyazaki Y, Hashimoto A, Hashimoto S, Mizuno R, Miyajima A, Okada Y, Sabe H, and Oya M
  • Journal Title: Urol Oncol Volume: 35(9) Issue: 9 Pages: 543.e17-543.e24
  • DOI: 10.1016/j.urolonc.2017.04.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Upregulation of eIF4A/4E-dependent mRNA translation is the major target of KRAS signaling (2019)
  • Author(s): Hashimoto A., Hashimoto S., Furukawa S., Tsutaho A., Fukao A., Onodera Y., Handa H., Oikawa T., Hata S., Nishikawa Y., Mizukami Y., Kodama Y., Murakami M., Fujiwara T., Hirano S., and Sabe H.
  • Organizer: 第19回蛋白質科学・第71回日本細胞生物合同年次大会、神戸
• [Presentation] Pancreatic KRAS/TP53 mutations promote ARF6-based immune evasion via activating mRNA translation and protein prenylation (2019)
  • Author(s): Hashimoto A., Hashimoto S., Furukawa S., Tsutaho A., Fukao A., Onodera Y., Handa H., Oikawa T., Hata S., Nishikawa Y., Mizukami Y., Kodama Y., Murakami M., Fujiwara T., Hirano S., and Sabe H.
  • Organizer: 第78回日本癌学会学術総会, 京都
• [Presentation] Arid5a orchestrates immunosuppressive environments via the Ido1-kynurenine-Treg axis in malignant pancreatic cancer (2019)
  • Author(s): Parajuli G., Hashimoto S., and Kishimoto T.
  • Organizer: 第48回日本免疫学会学術集会, 浜松
• [Presentation] Pancreatic KRAS and TP53 oncogenes cooperatively activate ARF6-AMAP1 pathway to drive malignancy and immune evasion (2018)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Shotaro Furukawa, Akio Tsutaho, Yasuhito Onodera, Yutaro Otsuka, Haruka Handa, Tsukasa Oikawa, Yusuke Mizukami, Masaaki Murakami, Satoshi Hirano, and Hisataka Sabe
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] メバロン酸代謝活性とArf6による癌悪性度進展の分子機序並びにスタチン有効性の解析 (2017)
  • Author(s): 橋本あり、橋本茂、及川司、大塚勇太郎、半田悠、小野寺康仁、佐邊壽孝
  • Organizer: 第116回北海道癌談話会
• [Presentation] 膵癌ドライバー変異はARF6経路を介して癌悪性度とPD-L1発現を促進する (2017)
  • Author(s): 橋本あり、橋本茂、古川聖太郎、蔦保暁生、大塚勇太郎、半田悠、小野寺康仁、及川司、平野聡、佐邊壽孝
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Patent(Industrial Property Rights)] 新規な消化器がん治療剤およびそのスクリーニング方法 (2020)
  • Inventor(s): PCT/JP2020/ 021278
  • Industrial Property Rights Holder: PCT/JP2020/ 021278
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] 新規な膵がん治療剤およびそのスクリーニング方法 (2019)
  • Inventor(s): 岸本忠三、橋本茂
  • Industrial Property Rights Holder: 岸本忠三、橋本茂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 癌免疫療法併用剤 (2019)
  • Inventor(s): 佐邊壽孝、平野聡、橋本あり、橋本茂
  • Industrial Property Rights Holder: 佐邊壽孝、平野聡、橋本あり、橋本茂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] 癌免疫療法併用剤 (2018)
  • Inventor(s): 佐邊壽孝、平野聡、橋本あり、橋本茂
  • Industrial Property Rights Holder: 佐邊壽孝、平野聡、橋本あり、橋本茂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-048179
  • Filing Date: 2018