The intracellular signaling of Midkine in neuroblastoma

• Project/Area Number: 16K08617
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: Kishida Satoshi 名古屋大学, 医学系研究科, 講師 (20402563)
• Co-Investigator(Kenkyū-buntansha): 坂元 一真 名古屋大学, 医学系研究科, 助教 (60612801)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 神経芽腫 / Midkine / 骨髄転移 / 線維芽細胞 / シスプラチン / 細胞内シグナル伝達 / 薬剤耐性

Outline of Final Research Achievements

Midkine, a secreted growth factor, was shown to be involved in cisplatin resistance of bone marrow-metastasized neuroblastoma cells. The midkine-targetting therapy together with cisplatin could efficiently kill bone marrow-metastasized neuroblastma cells. We also found that mouse embryonic fibroblast (MEF) remarkably responded to midkine. This result suggests that midkine would signal not only to neuroblastoma cells but also stromal cells including fibroblasts.

Academic Significance and Societal Importance of the Research Achievements

神経芽腫の治療において、最も致命的となるのは「再発」であり、好再発部位の一つが骨髄である。つまり、悪性度の高い神経芽腫細胞にとって、原発部位よりもむしろ、骨髄の環境の方が幸便であることが推察される。この骨髄に転移した神経芽腫細胞を効果的に叩く治療法が開発されればインパクトがあるが、本研究で明らかにしたMidkineの機能は、その大きなヒントを与えていると考えられる。Midkineが、骨髄に転移した神経芽腫細胞のシスプラチン耐性誘導に寄与している可能性が示唆されたため、その働きを阻害することで、シスプラチン薬効の奏功を期待できる。

Research Products

• [Journal Article] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. (2017)
  • Author(s): 1.Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106296-106310
  • DOI: 10.18632/oncotarget.22435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma (2017)
  • Author(s): 2.Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K.
  • Journal Title: Cancer Res. Volume: 77 Issue: 19 Pages: 5259-5271
  • DOI: 10.1158/0008-5472.can-16-3144
  • Peer Reviewed
• [Journal Article] Temporally and Spatially Regulated Expression of the Linker Histone H1fx During Mouse Development. (2017)
  • Author(s): Ichihara-Tanaka K, Kadomatsu K, Kishida S.
  • Journal Title: J Histochem Cytochem Volume: 65 Issue: 9 Pages: 513-530
  • DOI: 10.1369/0022155417723914
  • Peer Reviewed
• [Journal Article] A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-κB degradation and cell growth suppression in neuroblastoma. (2017)
  • Author(s): Mu P, Akashi T, Lu F, Kishida S, Kadomatsu K.
  • Journal Title: Oncogene Volume: 36 Issue: 41 Pages: 5745-5756
  • DOI: 10.1038/onc.2017.181
  • Peer Reviewed
• [Journal Article] SGO1 is involved in the DNA damage response in MYCN-amplified neuroblastoma cells. (2016)
  • Author(s): Murakami-Tonami Y, Ikeda H, Yamagishi R, Inayoshi M, Inagaki S, Kishida S, Komata Y, Jan Koster, Takeuchi I, Kondo Y, Maeda T, Sekido Y, Murakami H, Kadomatsu K.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 31615-31615
  • DOI: 10.1038/srep31615
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease. (2016)
  • Author(s): Honda Y, Shishido T, Takahashi T, Watanabe T, Netsu S, Kinoshita D, Narumi T, Kadowaki S, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Kishida S, Kadomatsu K, Takeishi Y, Kubota I.
  • Journal Title: Hypertension. Volume: 67(5) Issue: 5 Pages: 857-865
  • DOI: 10.1161/hypertensionaha.115.06922
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Neurocan, a chondroitin sulfate proteoglycan, is a crucial extracellular component in neuroblastoma tissues, which promotes malignant phenotypes (2018)
  • Author(s): Satoshi Kishida, Kenji Kadomatsu
  • Organizer: Advances in Neuroblastoma Research 2018
  • Int'l Joint Research
• [Presentation] Cited2 suppresses tumor formation and metastasis of neuroblastoma through inhibition of the CBP/p300-β-catenin-Sox9 axis (2017)
  • Author(s): Satoshi Kishida, Dongliang Cao, Peng Huang, Zhendong Su, Ichiro Takeuchi, Masato Nakaguro, Shoma Tsubota, Atsushi Narita, Yinyan Xu, Yasuko Yoshida, Yoshiyuki Takahashi, Kenji Kadomatsu
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. (2017)
  • Author(s): Kishida S, Su Z, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K
  • Organizer: Asia-Pacific Symposium of Neuroblastoma 2017
  • Int'l Joint Research
• [Presentation] The involvement of Midkine, a growth factor exacerbating cisplatin-induced nephrotoxicity, in cisplatin resistance of neuroblastoma cells (2016)
  • Author(s): Satoshi Kishida, Kenji Kadomatsu
  • Organizer: Advances in Neuroblastoma Research 2016
  • Place of Presentation: Cairns (Australia)
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Remarks] 名古屋大学大学院医学系研究科生物化学講座分子生物学
  • URL: https://www.med.nagoya-u.ac.jp/medical_J/laboratory/basic-med/bio-chem/mol-biology/