Regulation of cellular function by intracellular/intranuclear amino acids

• Project/Area Number: 17K19555
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pathology, Infection/Immunology, and related fields
• Research Institution: Osaka University
• Principal Investigator: Morii Eiichi 大阪大学, 医学系研究科, 教授 (10283772)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 腫瘍 / 遺伝子発現 / 腫瘍代謝 / アミノ酸 / ピルビン酸代謝 / 活性酸素 / 細胞増殖 / 光学異性体 / 腫瘍悪性度 / 腫瘍幹細胞 / 細胞機能

Outline of Final Research Achievements

We revealed that various amino acids regulated cellular function especially in gene expression. Here, we evaluated the function of serine racemase, which converts D-from to L-form of serine. We found that serine racemase was highly expressed in colon adenocarcinoma as compared to adjacent normal colon mucosa. Pyruvate, which is important in energy production, was synthesized from serine via serine racemase. In addition, serine racemase played an important role in gene expression with epigenetic manner. Through these results, we revealed that amino acids are not only component of protein or peptide but also function as a metabolite regulating cellular function especially in gene regulation.

Academic Significance and Societal Importance of the Research Achievements

アミノ酸は従来、タンパク質やペプチドの構成体としてしか考えられていなかったが、それ以外にも様々な細胞機能に関与することが明らかにされつつある。本研究では、これまでアルギニン代謝が腫瘍の悪性化に重要であることを明らかにしており、さらに今回、エネルギー代謝に重要な役割を担うピルビン酸の産生にもセリンの光学異性体を変換する物質が関与することを新たに見出し、これらが遺伝子発現をも制御していることを報告した。アミノ酸の様々な機能を明らかにしており、これらは新たな腫瘍治療のターゲットとなりうる。

Research Products

• [Journal Article] Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine (2020)
  • Author(s): Kenji Ohshima, Satoshi Nojima, Shinichiro Tahara, Masako Kurashige, Keisuke Kawasaki, Yumiko Hori, Moyu Taniguchi, Yutaka Umakoshi, Daisuke Okuzaki, Naoki Wada, Jun-ichiro Ikeda, Eiichiro Fukusaki & Eiichi Morii
  • Journal Title: Nature Metabolism volume Volume: 2 Issue: 1 Pages: 81-96
  • DOI: 10.1038/s42255-019-0156-2
  • Peer Reviewed
• [Journal Article] Tumour Grade Significantly Correlates With Total Dysfunction of Tumour Tissue-Infiltrating Lymphocytes in Renal Cell Carcinoma (2020)
  • Author(s): Kawashima A, Kanazawa T, Kidani Y, Yoshida T, Hirata M, Nishida K, Nojima S, Yamamoto Y, Kato T, Hatano K, Ujike T, Nagahara A, Fujita K, Morimoto-Okazawa A, Iwahori K, Uemura M, Imamura R, Ohkura N, Morii E, Sakaguchi S, Wada H, Nonomura N.
  • Journal Title: Sci Rep . Volume: 10 Issue: 1 Pages: 6220-6220
  • DOI: 10.1038/s41598-020-63060-1
  • Peer Reviewed / Open Access
• [Journal Article] SDPR Regulates ALDH1 via ILK Signaling in Endometrioid Carcinoma Cells. (2019)
  • Author(s): Tahara S, Nojima S, Ohshima K, Hori Y, Kurashige M, Wada N, Motoyama Y, Okuzaki D, Ikeda JI, Morii E.
  • Journal Title: Cancer Sci. Volume: in press Issue: 5 Pages: 1804-1813
  • DOI: 10.1111/cas.14007
  • Peer Reviewed / Open Access
• [Journal Article] Origin of cancer-associated fibroblasts and tumor-associated macrophages in humans after sex-mismatched bone marrow transplantation. (2018)
  • Author(s): Kurashige M, Kohara M, Ohshima K, Tahara S, Hori Y, Nojima S, Wada N, Ikeda JI, Miyamura K, Ito M, Morii E.
  • Journal Title: Commun Biol. Volume: 1 Issue: 1 Pages: 131-131
  • DOI: 10.1038/s42003-018-0137-0
  • Peer Reviewed / Open Access
• [Journal Article] Effect of glutamine on lymphoplasmacytic lymphoma, especially on the viewpoint of the differentiation into vulnerable subpopulation. (2018)
  • Author(s): Wada N, Nojima S, Tahara SI, Ohshima K, Kurashige M, Kawasaki K, Tone M, Kusumoto S, Ikeda JI, Morii E.
  • Journal Title: Pathol Res Pract Volume: 214 Issue: 10 Pages: 1667-1674
  • DOI: 10.1016/j.prp.2018.08.019
  • Peer Reviewed / Open Access
• [Journal Article] Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate (2018)
  • Author(s): Park Haengki、Ohshima Kenji、Nojima Satoshi、Tahara Shinichiro、Kurashige Masako、Hori Yumiko、Okuzaki Daisuke、Wada Naoki、Ikeda Jun-ichiro、Morii Eiichi
  • Journal Title: Lab Invest Volume: in press Issue: 4 Pages: 449-461
  • DOI: 10.1038/s41374-017-0017-0
  • Peer Reviewed / Open Access
• [Journal Article] Detection of epidermal growth factor receptor mutations in lung adenocarcinoma cytological specimens by immunocytochemistry (2017)
  • Author(s): Yoshida Masami、Nagatomo Tadasuke、Ohnishi Takafumi、Kawashima Mayumi、Naitoh Akira、Morii Eiichi
  • Journal Title: Mol Clin Oncol Volume: 7 Pages: 981-987
  • DOI: 10.3892/mco.2017.1451
  • Peer Reviewed
• [Journal Article] Usefulness of cytological analysis in the diagnosis of pancreatic undifferentiated rhabdoid carcinoma (2017)
  • Author(s): Tahara Shinichiro、Takeyari Misa、Morii Eiichi
  • Journal Title: Pathology International Volume: 68 Issue: 1 Pages: 56-58
  • DOI: 10.1111/pin.12616
  • Peer Reviewed
• [Journal Article] ALDH enzyme activity is regulated by Nodal and histamine in the A549 cell line (2017)
  • Author(s): Jiang Yang、Li Hui、Wang Yi、Tian Tian、He Yan、Jin Yinji、Han Changsong、Jin Xiaoming、Zhang Fengmin、Morii Eiichi
  • Journal Title: Oncol Lett14 Volume: 14 Pages: 6955-6961
  • DOI: 10.3892/ol.2017.7057
  • Peer Reviewed
• [Journal Article] The activated conformation of integrin β7 as a target for multiple myeloma-specific chimeric antigen receptor T cell therapy. (2017)
  • Author(s): Hosen N, Matsunaga Y, Hasegawa K, Matsuno H, Nakamura Y, Makita M, Watanabe K, Yoshida M, Satoh K, Morimoto S, Fujiki F, Nakajima H, Nakata J, Nishida S, Tsuboi A, Oka Y, Manabe M, Ichihara H, Aoyama Y, Mugitani A, Nakao T, Hino M, Uchibori R, Ozawa K, Baba Y, et al.
  • Journal Title: Nat. Med. Volume: 23 Issue: 12 Pages: 1436-1443
  • DOI: 10.1038/nm.4431
  • Peer Reviewed
• [Journal Article] CUBIC pathology: three-dimensional imaging for pathological diagnosis (2017)
  • Author(s): Nojima Satoshi、Susaki Etsuo A.、Yoshida Kyotaro、Takemoto Hiroyoshi、Tsujimura Naoto、Iijima Shohei、Takachi Ko、Nakahara Yujiro、Tahara Shinichiro、Ohshima Kenji、Kurashige Masako、Hori Yumiko、Wada Naoki、Ikeda Jun-ichiro、Kumanogoh Atsushi、Morii Eiichi、Ueda Hiroki R.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 9269-9269
  • DOI: 10.1038/s41598-017-09117-0
  • Peer Reviewed / Open Access
• [Journal Article] Non-labeling multiphoton excitation microscopy as a novel diagnostic tool for discriminating normal tissue and colorectal cancer lesions (2017)
  • Author(s): Matsui Takahiro、Mizuno Hiroki、Sudo Takao、Kikuta Junichi、Haraguchi Naotsugu、Ikeda Jun-ichiro、Mizushima Tsunekazu、Yamamoto Hirofumi、Morii Eiichi、Mori Masaki、Ishii Masaru
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 6959-6959
  • DOI: 10.1038/s41598-017-07244-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Massive tumor embolism in the abdominal aorta from pulmonary squamous cell carcinoma: Case report and review of the literature (2017)
  • Author(s): Ohshima Kenji、Tsujii Yuri、Sakai Kazuya、Oku Hiroshi、Morii Eiichi
  • Journal Title: Pathology International Volume: 67 Issue: 9 Pages: 467-471
  • DOI: 10.1111/pin.12554
  • Peer Reviewed
• [Journal Article] Effect of plasma-activated medium on the decrease of tumorigenic population in lymphoma (2017)
  • Author(s): Wada Naoki、Ikeda Jun-ichiro、Tanaka Hiromasa、Sakakita Hajime、Hori Masaru、Ikehara Yuzuru、Morii Eiichi
  • Journal Title: Pathol Res Pract Volume: 213 Issue: 7 Pages: 773-777
  • DOI: 10.1016/j.prp.2017.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer. (2017)
  • Author(s): Ohshima K, Nojima S, Tahara S, Kurashige M, Hori Y, Hagiwara K, Okuzaki D, Oki S, Wada N, Ikeda JI, Kanai Y, Morii E.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 45504-45504
  • DOI: 10.1038/srep45504
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 病理診断におけるAIと専門医のあり方 (2019)
  • Author(s): 森井英一
  • Organizer: 日本学術会議公開シンポジウム
  • Invited
• [Presentation] 変遷する腫瘍の源 (2018)
  • Author(s): 森井英一
  • Organizer: 第15回日本病理学会カンファレンス
  • Invited
• [Presentation] がん幹細胞の病理 (2017)
  • Author(s): 森井英一
  • Organizer: 日本病理学会
  • Invited
• [Presentation] コンパニオン診断の実際 現状と今後 (2017)
  • Author(s): 森井英一
  • Organizer: 日本臨床細胞学会
  • Invited
• [Remarks] 大腸がんの創薬ターゲットになり得る新規がん代謝経路を発見
  • URL: https://resou.osaka-u.ac.jp/ja/research/2020/20200120_2