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Kenji Kadomatsu MD, PhDProfessor, Department of Molecular Biology, Nagoya University Graduate School of Medicine

Specialized field


Career Summary

Graduate student, Kyushu University Graduate School of Medicine(Discovery of the growth factor midkine)
Research associate, Kagoshima University Faculty of Medicine(Analysis of the biological functions of midkine, particularly in cancer)
Research associate, Assistant professor, Associate professor, Nagoya University Graduate School of Medicine(Application of midkine to clinical use, particularly for cardiovascular disease, carcinomas and inflammatory diseases; Discovery of the critical roles of basigin in genesis of the retina and sex organ; Discovery of the biological roles of keratan sulfate in inhibition of neuronal axon regeneration)
Professor, Nagoya University Graduate School of Medicine

Research Theme

Carcinogenesis and remodeling after neuronal injury

Research Summary

Neuroblastoma tumorigenesis and neuronal circuit reconstruction

A. Aim
Pediatric cancers occur shortly after birth. They may require simpler process for their tumorigenesis as compared with adult cancers. Therefore, pediatric cancers could be a good model to study tumorigenesis. Neuroblastoma is the most popular but treatment-resistant pediatric solid tumor, and is originated from neuron. In other words, neuroblastoma could be a subject merging neuronal differentiation and tumorigenesis. We will focus on early stage of tumorigenesis of neuroblastoma. The second topic is neuronal circuit reconstruction. Neural plasticity, including axonal regeneration and re-formation of synapses, is involved in the repair processes after neuronal injuries. We will focus on action mechanism of the inhibitory factor proteoglycan.

B. Achievements
(1) Tumorigenesis of neuroblastoma
Regarding tumorigenesis, it is of note that MYCN transgenic (Tg) mice show hyperplasia (clusters of small round neuroblasts) in sympathetic ganglion 2 weeks after birth. Based on expression profiles of genes, we speculate that this is a precancerous lesion. In this study, we examined molecules whose expressions change during tumorigenesis of MYCN Tg mice and show significant association of patient prognosis.
We reported that NeuroD1 is the factor with a function bridging neural development and neuroblastoma (Huang et al., Cancer Res, 2011). NeuroD1 is known to be a regulator of neurogenesis and maintenance of neural progenitors. We found that it was highly expressed in hyperplasia of neuroblasts and was expressed in advanced tumors. Knockdown of NeuroD1 expression led to tumor suppression. Furthermore, high NeuroD1 expression was associated with poor prognosis of neuroblastoma patients. We also found several interesting molecules. One of them is related to stemness of neuroblastoma. Another challenge is to screen for molecular targets of neuroblastoma therapy based on the concept synthetic lethality. Data obtained so far provide us with insight into mechanisms supporting neuroblastoma development.
(2) Neuronal circuit reconstruction
Chondroitin sulfate proteoglycan (CSPG) has been implicated in suppression of axonal regeneration/sprouting. We have been studying on another proteoglycan, keratan sulfate proteoglycan (KSPG). We reported that KS-deficient mice exhibit enhanced axonal regeneration/sprouting after neuronal injuries. We also found that a KS-degrading enzyme promotes functional recovery after spinal cord injury (Imagama et al., J Neurosci, 2011). In vitro experiments including neurite outgrowth on proteoglycan indicated that CS or KS alone does not inhibit neurite outgrowth. The inhibitory activity was lost by heat-inactivation of proteoglycans or replacement of core protein with artificial one. Furthermore, a core protein-degrading enzyme promoted axonal regeneration/sprouting in vitro and in vivo (Tauchi et al., J Neuroinflammation, 2012). Taken together, our data suggest that an appropriate presentation of KS and/or CS chains by core protein is essential for the proteoglycan-mediated inhibition of axonal regeneration/sprouting (Figure).

Principal Research Achievement

  1. Tauchi R, Imagama S, Ohgomori T, Natori T, Shinjo R, Ishiguro N, Kadomatsu K: ADAMTS-13 is produced by glial cells and upregulated after spinal cord injury. Neurosci Lett, in press (2012)
  2. Tauchi R, Imagama S, Natori T, Ohgomori T, Muramoto A, Shinjo R, Matsuyama Y, Ishiguro N, Kadomatsu K: The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. J Neuroinflammation, 9, 53 (2012)
  3. Sonobe Y, Li H, Jin S, Kishida S, Kadomatsu K, Takeuchi H, Mizuno T, Suzumura A: Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells. J Immunol, 188, 2602-2611 (2012)
  4. Sakai K, Yamamoto A, Matsubara K, Nakamura S, Naruse M, Yamagata M, Sakamoto K, Tauchi R, Wakao N, Imagama S, Hibi H, Kadomatsu K, Ishiguro N, Ueda M: Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. J Clin Invest, 122, 80-90 (2012)
  5. Inaba S, Nagahara S, Makita N, Tarumi Y, Ishimoto T, Matsuo S, Kadomatsu K, Takei Y: Atelocollagen-mediated systemic delivery prevents immunostimulatory adverse effects of siRNA in mammals. Mol Ther, 20, 356-366 (2012)
  6. Imagama S, Sakamoto K, Tauchi R, Shinjo R, Ohgomori T, Ito Z, Zhang H, Nishida Y, Asami N, Takeshita S, Sugiura N, Watanabe H, Yamashita T, Ishiguro N, Matsuyama Y, Kadomatsu K: Keratan sulfate restricts neural plasticity after spinal cord injury. J Neurosci, 31, 17091-17102 (2011)
  7. Huet E, Vallee B, Delbe J, Mourah S, Pruliere-Escabasse V, Tremouilleres M, Kadomatsu K, Doan S, Baudouin C, Menashi S, Gabison EE: EMMPRIN modulates epithelial barrier function through a MMP-mediated occludin cleavage: implications in dry eye disease. Am J Pathol, 179, 1278-1286 (2011)
  8. Ishiguro H, Horiba M, Takenaka H, Sumida A, Opthof T, Ishiguro YS, Kadomatsu K, Murohara T, Kodama I: A single intracoronary injection of midkine reduces ischemia/reperfusion injury in Swine hearts: a novel therapeutic approach for acute coronary syndrome. Front Physiol, 2, 27 (2011)
  9. Hayashi M, Kadomatsu K, Kojima T, Ishiguro N: Keratan sulfate and related murine glycosylation can suppress murine cartilage damage in vitro and in vivo. Biochem Biophys Res Commun, 409, 732-737 (2011)
  10. Kato K, Kosugi T, Sato W, Arata-Kawai H, Ozaki T, Tsuboi N, Ito I, Tawada H, Yuzawa Y, Matsuo S, Kadomatsu K, Maruyama S: Growth factor Midkine is involved in the pathogenesis of renal injury induced by protein overload containing endotoxin. Clin Exp Nephrol, 15, 346-354 (2011)
  11. Wakao N, Imagama S, Zhang H, Tauchi R, Muramoto A, Natori T, Takeshita S, Ishiguro N, Matsuyama Y, Kadomatsu K: Hyaluronan oligosaccharides promote functional recovery after spinal cord injury in rats. Neurosci Lett, 488, 299-304 (2011)
  12. Kadomatsu K: Proteoglycans and neural circuit reconstruction. Seikagaku, 83, 240-246 (2011)
  13. Kato N, Kosugi T, Sato W, Ishimoto T, Kojima H, Sato Y, Sakamoto K, Maruyama S, Yuzawa Y, Matsuo S, Kadomatsu K: Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction. Am J Pathol, 178, 572-579 (2011)
  14. Sakamoto K, Bu G, Chen S, Takei Y, Hibi K, Kodera Y, McCormick LM, Nakao A, Noda M, Muramatsu T, Kadomatsu K: Premature ligand-receptor interaction during biosynthesis limits the production of growth factor midkine and its receptor LDL receptor-related protein 1. J Biol Chem, 286, 8405-8413 (2011)
  15. Huang P, Kishida S, Cao D, Murakami-Tonami Y, Mu P, Nakaguro M, Koide N, Takeuchi I, Onishi A, Kadomatsu K: The neuronal differentiation factor NeuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma. Cancer Res, 71, 2938-2948 (2011)
  16. Wakao N, Imagama S, Tauchi R, Muramoto A, Zhang H, Natori T, Takeshita S, Ishiguro N, Matsuyama Y, Kadomatsu K: Hyaluronan oligosaccharides promote functional recovery after spinal cord injury in rats. Neurosci Lett, 488, 299-304 (2010)
  17. Hayashi M, Kadomatsu K, Ishiguro N: Keratan sulfate suppresses cartilage damage and ameliorates inflammation in an experimental mice arthritis model. Biochem Biophys Res Commun, 401, 463-468 (2010)
  18. Miwa Y, Yamamoto K, Onishi A, Iwamoto M, Yazaki S, Haneda M, Iwasaki K, Liu D, Ogawa H, Nagasaka T, Uchida K, Nakao A, Kadomatsu K, Kobayashi T: Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. Xenotransplantation, 17, 26-37 (2010)
  19. Ito Z, Sakamoto K, Imagama S, Matsuyama Y, Zhang H, Hirano K, Ando K, Yamashita T, Ishiguro N, Kadomatsu K. N-acetylglucosamine 6-O-sulfotransferase-1-deficient Mice Show Better Functional Recovery after Spinal Cord Injury. J Neurosci, 30, 5937-5947 (2010)
  20. Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K. DDR1 is expressed in the developing nervous system and downregulated during neuroblastoma carcinogenesis. Biochem Biophys Res Commun, 394, 829-835 (2010)
  21. Kadomatsu K. Midkine Regulation of the Renin-Angiotensin System. Curr Hypertens Rep, 12, 74-79 (2010)
  22. Sumida A, Horiba M, Ishiguro H, Takenaka H, Ueda N, Ooboshi H, Opthof T, Kadomatsu K, Kodama I. Midkine Gene Transfer after Myocardial Infarction in Rats Prevents Remodeling and Ameliorates Cardiac Dysfunction. Cardiovasc Res, 86, 113-121 (2010)
  23. Hobo A, Yuzawa Y, Kosugi T, Kato N, Asai N, Sato W, Maruyama S, Ito Y, Kobori H, Ikematsu S, Nishiyama A, Matsuo S, Kadomatsu K. The growth factor midkine regulates the renin-angiotensin system in mice. J Clin Invest, 119, 1616-1625 (2009)
  24. Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu K, Takei Y. Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer, 125, 2978-2990 (2009)
  25. Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W, Miwa Y, Sakamoto K, Matsuo S, Kadomatsu K. The E-selectin ligand Basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion. J Am Soc Nephrol, 20, 1565-1576 (2009)
  26. Yin J, Sakamoto K, Zhang H, Ito Z, Imagama S, Kishida S, Natori T, Sawada M, Matsuyama Y, Kadomatsu K. Transforming growth factor-β1 upregulates keratan sulfate and chondroitin sulfate biosynthesis in microglias after brain injury. Brain Res, 1263, 10-22 (2009)
  27. Sakakima H, Yoshida Y, Yamazaki Y, Matsuda F, Ikutomo M, Ijiri K, Muramatsu H, Muramatsu T, Kadomatsu K. Disruption of the midkine gene (Mdk) delays degeneration and regeneration in injured peripheral nerve. J Neurosci Res, 87, 2908-2915 (2009)
  28. Takenaka H, Horiba M, Ishiguro H, Sumida A, Hojo M, Usui A, Akita T, Sakuma S, Ueda Y, Kodama I, Kadomatsu K. Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction. Am J Physiol Heart Circ Physiol, 296, H462-469 (2009)
  29. Ishimoto T, Takei Y Yuzawa Y, Hanai K, Nagahara S, TarumiY, Matsuo S, Kadomatsu K. Downregulation of monocyte chemoattractant protein-1 involving short interfering RNA attenuates Hapten-induced contact hypersensitivity. Mol Ther, 16, 387-395 (2008)
  30. Takei Y, Nemoto T, Mu P, Fujishima T, Ishimoto T, Hayakawa Y, Yuzawa Y, Matsuo S, Muramatsu T, Kadomatsu K. In vivo silencing of a molecular target by short interfering RNA electroporation: Tumor vascularization correlates to delivery efficiency. Mol Cancer Ther, 7, 211-221 (2008)
  31. Maekawa F, Minehira K, Kadomatsu K, Pellerin L. Basal and stimulated lactate fluxes in primary cultures of astrocytes are differentially controlled by distinct proteins. J Neurochem, 107, 789-798 (2008)
  32. Ikematsu S, Nakagawara A, Nakamura Y, Ohira M, Shinjo M, Kishida S, Kadomatsu K. Plasma midkine leveli is a prognostic factor for human neuroblastoma. Cancer Sci, 99, 2070-2074 (2008)
  33. Narita H, Chen S, Komori K, Kadomatsu K. Midkine is expressed by infiltrating macrophages in in-stent restenosis in hypercholesterolemic rabbits. J Vas Surg, 47, 1322-1329 (2008)
  34. Kosugi T et al. Midkine is involved in tubulo-interstitial inflammation associated with diabetic nephropathy. Lab. Invest. 87: 903-913 (2007)
  35. Chen S et al. Midkine and LDL receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells. J. Cell Sci. 120: 4009-4015 (2007)
  36. Horiba M et al. Midkine plays a protective role against cardiac ischemia/reperfusion injury through a reduction of apoptotic reaction. Circulation 114: 1713-1720 (2006)
  37. Zhang H et al. N-acetylglucosamine 6-O-sulfotransferase-1 is required for brain keratan sulfate biosynthesis and glial scar formation after brain injury. Glycobiology 16: 702-710 (2006)
  38. Kawashima H et al. N-Acetylglucosamine-6-O-sulfotransferase-1 and -2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat. Immunol. 6: 1096-1104 (2005)
  39. Takei Y et al. A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res. 64: 3365-3370 (2004)
  40. Uchimura K et al. N-acetylglucosamine 6-O-sulfotransferase-1 regulates expression of L-selectin ligands and lymphocyte homing. J. Biol. Chem. 279: 35001-35008 (2004)
  41. Suzuki N et al. Proteasomal degradation of the nuclear targeting growth factor midkine. J. Biol. Chem. 279: 17785-17791 (2004)
  42. Shibata Y et al. Nuclear targeting by the growth factor midkine. Mol. Cell. Biol. 22: 6788-6796 (2002)
  43. Takei Y et al. Antisense oligonucleotide targeted to midkine, a heparin-binding growth factor, suppresses tumorigenicity of mouse rectal carcinoma cells. Cancer Res. 61: 8486-8491 (2001)
  44. Sato W et al. Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury. J. Immunol. 167: 3463-3469 (2001)
  45. Qi M et al. Haptotactic migration induced by midkine: Involvement of protein-tyrosine phosphatase ζ, mitogen-activated protein kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 276: 15868-15875 (2001)
  46. Ishiguro K et al. Complete antithrombin deficiency in mice results in embryonic lethality. J. Clin. Invest. 106: 873-878 (2000)
  47. Horiba M et al. Neointima formation in a restenosis model is suppressed in midkine-deficient mice. J. Clin. Invest. 105: 489-495 (2000)
  48. Uchimura K et al. Molecular cloning and characterization of an N-acetylglucosamine-6-O-sulfotransferase. J. Biol. Chem. 273: 22577-22583 (1998)
  49. Kadomatsu K et al. Expression of sulfated glycoprotein 2 is associated with carcinogenesis induced by N-nitroso-N-methylurea in rat prostate and seminal vesicle. Cancer Res. 53: 1480-1483 (1993)
  50. Tsutsui J et al. A new family of heparin-binding growth differentiation factors: Increased midkine expression in Wilms' tumor and other human carcinomas. Cancer Res. 53: 1281-1285 (1993)
  51. Kadomatsu K et al. A retinoic acid responsive gene, MK, found in the teratocarcinoma system is expressed in spatially and temporally controlled manner during mouse embyogenesis. J. Cell Biol. 110: 607-616 (1990)


Young Investigator Award of Japanese Biochemical Society (1997)