Anti-tumor effects and Regulation of Wnt signaling pathway of adenovirus-mediated DKK3 in glioblastoma

• Project/Area Number: 25462264
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: The University of Tokushima
• Principal Investigator: MIZOBUCHI Yoshifumi 徳島大学, 大学病院, 講師 (80547993)
• Co-Investigator(Kenkyū-buntansha): MURE Hideo 徳島大学, 大学院医歯薬学研究部, 助教 (00624355) ; NAGAHIRO Shinji 徳島大学, 大学院医歯薬学研究部, 教授 (60145315) ; KAGEJI Teruyoshi 徳島大学, 病院, 特任教授 (70294684) ; KUWAYAMA Kazuyuki 四国こどもとおとなの医療センター, 臨床研究部, 脳神経外科医長 (50614236) ; NAKAJIMA Kohei 徳島大学, 病院, 助教 (40710554) ; HARA Keijirou 徳島大学, 病院, 助教 (60710340)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 脳腫瘍 / グリオブラストーマ / Wnt / DKK3 / 遺伝子治療 / ｸﾞﾘｵﾌﾞﾗｽﾄｰﾏ / 悪性脳腫瘍 / Ad-REIC / Wntシグナル

Outline of Final Research Achievements

The effect of the third member of the Dickkopf family (DKK3) in the Wnt pathway in glioblastoma remains unclear. We first demonstrated the non-specific interaction of Wnt3a and Wnt5a with the receptors LRP6 and ROR2 and the up-regulation of the Wnt pathway in glioblastoma cells. We used an adenovirus vector and found that an increase in DKK3 protein attenuated the expression of Wnt3a, Wnt5a and LRP6, but not of ROR2, and their interaction, thereby affecting both canonical- and non-canonical Wnt downstream cascades. This produced anti-tumor effects in GBM xenograft models. The suppression of Wnt pathways upstream by DKK3 may have promise for the treatment of glioblastoma.

Research Products

• [Journal Article] Blocking of the interaction between Wnt proteins and their co-receptors contributes to the anti-tumor effects of adenovirus-mediated DKK3 in glioblastoma (2015)
  • Author(s): Hara K, Kageji T, Mizobuchi Y, Kitazato KT, Okazaki T, Fujihara T, Nakajima K, Mure H, Kuwayama K, Hara T, Nagahiro S
  • Journal Title: Cancer Lett Volume: 356 Issue: 2 Pages: 496-505
  • DOI: 10.1016/j.canlet.2014.09.045
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis of brain tumors using dynamic contrast-enhanced perfusion imaging with a short acquisition time (2015)
  • Author(s): Abe T, Mizobuchi Y, Nakajima K, Otomi Y, Irahara S, Obama Y, Majigsuren M, Khashbat D, Kageji T, Nagahiro S, Harada M
  • Journal Title: Springerplus Volume: 4 Issue: 1 Pages: 88-88
  • DOI: 10.1186/s40064-015-0861-6
  • Peer Reviewed / Open Access
• [Presentation] Significance of temozolomide re-challenge after progression of malignant gliomas in maintaining performance status of the patients-multicenter cooperative study (2015)
  • Author(s): S.Kohno, T.Ohnishi, T.Ichikawa, I. Date, K.Miyake, T.Tomiya, T. Kageji, S,Nagahiro, M.Ideguchi, M.Suzuki, A.Kanbe, T.Watanabe, K.Miyazaki, Y.Akiyama, N.Matushita, M.Uno
  • Organizer: 20th Annual Socientific Meeting and Education Day of the Society for Neuro-Oncology
  • Place of Presentation: Texas, USA
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] Sonodynamic 5-ALA plus ultrasound therapy augments anti-tumor effects in the oncogene knock-in glioma stemcells (2015)
  • Author(s): K.Shono, T.Kageji, Y.Mizobuchi, T.Fujihara, K.Kitazato, K.Nakajima, H.Mure, K.Kuwayama, S.Nagahiro
  • Organizer: 20th Annual Socientific Meeting and Education Day of the Society for Neuro-Oncology,
  • Place of Presentation: Texas,USA
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] Down-regulation of MDR1 by DKK3 attenuates chemoresistance to temozolomide, and potentiates its anti-tumor effects (2015)
  • Author(s): T.Fujihara, T.Kageji, Y.Mizobuchi, R.Otsuka K.Kitazato, K.Hara, K.Shono, K.Nakajima H.Mure, K.Kuwayama, S.Nagahiro
  • Organizer: 20th Annual Socientific Meeting and Education Day of the Society for Neuro-Oncology
  • Place of Presentation: Texas, USA
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] Intensive chemotherapy followed by reduced radiation dose for intracranial non-germinomatous germ cell tumors (2015)
  • Author(s): T.Kageji, Y.Mizobuchi, K.Nakajima, S.Nagahiro, H.Watanabe, N.Inoue, K.Okamura, S.Kagami
  • Organizer: 20th Annual Socientific Meeting and Education Day of the Society for Neuro-Oncology
  • Place of Presentation: Texas, USA
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] Intensive chemotherapy followed by reduced radiation dose for intracranial non-germinomatous germ cell tumors (2015)
  • Author(s): T. Kageji, Y. Mizobuchi, K. Nakajima, S. Nagahiro, H. Watanabe, N. Inoue, K. Okamura, S. Kagami
  • Organizer: 13th Congress of the World Federatoin of Interventional and Therapeutic Neuroradiology
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] Strategy and Clinical Results for Intracranial Non-germinomatous Germ Cell Tumors Induced Intensive Chemotherapy (2015)
  • Author(s): T.Kageji, Y.Mizobuchi, K.Nakajima, S.Nagahiro H.Watanabe, N.Inoue, K.Okamura, S.Kagami
  • Organizer: The 4th International CNS Germ Cell Tumor Symposium
  • Place of Presentation: HAPPO-EN,Tokyo, minato-ku
  • Year and Date: 2015-04-12
• [Presentation] Intensive Chemotherapy Followed by Reduced Dose Radiation for Intracranial Non-germinomatous Germ Cell Tumors (2015)
  • Author(s): H.Watanabe, N.Inoue, K.Okamura, S.Nagahiro, Y.Mizobuchi, K.Nakajima,T.Kageji, S.Kagami
  • Organizer: The 4th International CNS Germ Cell Tumor Symposium
  • Place of Presentation: HAPPO-EN,Tokyo, minato-ku
  • Year and Date: 2015-04-12
• [Presentation] Dkk-3, one of Dickkopf (Dkk) family members, contributes to the anti-tumor effects in glioblastoma through regulation of both Wnt signal pathways (2013)
  • Author(s): K.Hara, T.Kageji, Y.Mizobuchi, K.T.Kitazato, T.Okazaki, T.Fujihara, K.Nakajima, H.Mure, K.Kuwayama, T.Hara, S.Nagahiro
  • Organizer: SNO 2013
  • Place of Presentation: Marriott Marquis Hotel (San Francisco, USA)
• [Presentation] Down-regulation of MDR by Ad-Dkk3 contributes to augment the chemotherapy by temozolomide (2013)
  • Author(s): K.Nakajima, K.Hara, T.Kageji, Y.Mizobuchi, K.T.Kitazato, T.Fujihara, K.Kuwayama, R.Otsuka, D K.Kung, S.Nagahiro
  • Organizer: SNO 2013
  • Place of Presentation: Marriott Marquis Hotel (San Francisco, USA)
• [Presentation] A combination of interferon-b and temozolomide augments anti-tumor effects through p73/YAP-mediated apoptosis by PML in glioblastoma (2013)
  • Author(s): Y.Mizobuchi, T.Okazaki, T.Kageji, K.Kuwayama, K.T.Kitazato, H.Mure, K.Hara, R.Morigaki, K.Matsuzaki, K.Nakajima, T.Fujihara, S.Nagahiro
  • Organizer: SNO 2013
  • Place of Presentation: Marriott Marquis Hotel (San Francisco, USA)