Wnt signaling promotes epithelial tubulogenesis through the regulation of cell morphology and proliferation

• Project/Area Number: 25860211
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Osaka University
• Principal Investigator: MATSUMOTO Shinji 大阪大学, 医学(系)研究科(研究院), 特任助教(常勤) (20572324)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: Wnt / EGF / Arｌ４ｃ / YAP/TAZ / 上皮管腔形成 / Arl4c / 上皮分岐管腔形成

Outline of Final Research Achievements

Co-stimulation with Wnt3a and EGF induced development of tubes consisting of rat intestinal epithelial cells (IEC6) by inducing expression of Arl4c in three-dimensional culture. Arl4c expression resulted in cell morphological change (extension) through the activation of Rac and inactivation of Rho properly, which promoted cell growth by inducing nuclear translocation of YAP/TAZ in leading cells. Arl4c was expressed in ureteric bud tips in the embryonic kidney and regulated ureteric buds tubulogenesis. Furthermore, immunohistochemical analyses revealed that Arl4c was strongly expressed at high frequencies in tumor lesions of colorectal and lung cancers. Arl4c was involved in migration, invasion and proliferation capabilities both in vitro and in vivo.

Research Products

• [Journal Article] A. Basolateral secretion of Wnt5a in polarized epithelial cells is required for apical lumen formation (2015)
  • Author(s): Yamamoto, H., Awada, C., Matsumoto, S., Kaneiwa, T., Sugimoto, T., Takao, T., and Kikuchi
  • Journal Title: J. Cell Sci. Volume: 128 Pages: 1051-1063
  • DOI: 10.1242/jcs.163683
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target (2015)
  • Author(s): Fujii, S., Matsumoto, S., Nojima, S. Morii, E., and Kikuchi, A.
  • Journal Title: Oncogene Volume: In press Issue: 37 Pages: 4834-4844
  • DOI: 10.1038/onc.2014.402
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures. (2014)
  • Author(s): Matsumoto, S., Fujii, S., Sato, A., Ibuka, S., Kagawa, Y., Ishii, M., and Kikuchi, A.
  • Journal Title: EMBO J Volume: 33 Issue: 7 Pages: 702-718
  • DOI: 10.1002/embj.201386942
  • Peer Reviewed
• [Journal Article] Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo. (2014)
  • Author(s): Kagawa Y, Matsumoto S, Kamioka Y, Mimori M, Naito Y, Ishii T, Okuzaki D, Nishida N, Maeda S, Naito A, Kikuta J, Nishikawa K, Nishimura J, Haraguchi N, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Ishii H, Doki Y, Matsuda M, Kikuchi A, Mori M, Ishii M
  • Journal Title: PLoS One Volume: 8 Issue: 12 Pages: e83629-e83629
  • DOI: 10.1371/journal.pone.0083629
  • Peer Reviewed / Open Access
• [Journal Article] Wnt5a signaling promotes apical and basolateral polarization of single epithelial cells. (2013)
  • Author(s): Gon, H., Fumoto, K., Ku, Y., Matsumoto, S., and Kikuchi, A.
  • Journal Title: Mol. Biol. Cell. Volume: 24 Issue: 23 Pages: 3764-3774
  • DOI: 10.1091/mbc.e13-07-0357
  • Peer Reviewed
• [Presentation] Wnt/β-カテニンシグナルは外分泌腺上皮の分岐と導管形成を制御する (2014)
  • Author(s): 松本真司
  • Organizer: 第87回 日本生化学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-18
• [Book] G. I. Research「消化管の再生医療」 (In vitro実験系を用いた上皮管腔組織形成の分子基盤の確立) (2014)
  • Author(s): 松本真司、菊池 章
  • Total Pages: 72
  • Publisher: 先端医学社
• [Book] プログレッシブ 生命科学 (細胞増殖・運動・死とがん) (2014)
  • Author(s): 菊池 章、 松本真司
  • Total Pages: 312
  • Publisher: 南山堂
• [Book] Wnt Signaling in Development and Disease: Molecular Mechanisms and Biological Functions (2014)
  • Author(s): Akira kikuchi, Shinji Matsumoto, Katsumi Fumoto, and Akira Sato
  • Total Pages: 472
  • Publisher: Wiley-Blackwell
• [Book] 生体の科学 特集 細胞接着の制御 (2013)
  • Author(s): 松本 真司、菊池 章
  • Total Pages: 292
  • Publisher: 医学書院
• [Remarks] 大阪大学大学院 医学系研究科 分子病態生化学
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/
• [Remarks] 新学術領域研究 上皮管腔組織形成
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/tubulology/
• [Remarks] 大阪大学大学院 医学系研究科 分子病態生化学
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/
• [Remarks] 上皮管腔組織形成
  • URL: http://www.med.osaka-u.ac.jp/pub/molbiobc/tubulology/
• [Patent(Industrial Property Rights)] Arl4c遺伝子の発現を抑制する物質又はタンパク質の活性を抑制する物質を含む、癌の治療の為の医薬組成物（核酸を含む） (2014)
  • Inventor(s): 菊池 章、松本 真司、藤井 慎介
  • Industrial Property Rights Holder: 菊池 章、松本 真司、藤井 慎介
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-05-13