Fragmented hyaluronan is an autocrine factor potentiating cancer cell invasion supported by HAS2 -CD44/hyaluronidase-2 system on the plasma membrane

2012 Fiscal Year Final Research Report

• Project/Area Number: 22390074
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Chiba University
• Principal Investigator: HARIGAYA Kenichi 千葉大学, 大学院・医学研究院, 教授 (40101894)
• Co-Investigator(Kenkyū-buntansha): KITAGAWA Motoo 千葉大学, 大学院・医学研究院, 准教授 (40262026)
• Project Period (FY): 2010 – 2012
• Keywords: 癌浸潤・転移、CD44 / 上皮-間葉転換(EMT) / ヒアルロン酸、がん治療

Research Abstract

Here we show that fragmented 23 kDa HA elicits enhanced cell motility and changes the shape of epithelial cells. Our study also indicates that hyaluronidase-2-mediated catabolism could play a significant role in the generation of LMWHA (about 20 kDa) with the association of CD44 in epithelial cells. This indicates the possibility that fragmented HA acts as a mediator in the autocrine/paracrine mechanism. Our study showed that signals initiated by LMWHA-CD44 interactions induce the phenotypes of cancer cells undergoing epithelial-mesenchymal transition (EMT), expanding our understanding of the functions of HA in cancer cell biology.

Research Products

• [Journal Article] Charac- terization of sarcoma-like cells derived from endarterectomized tissues from patients with CTEPH and establishment of a mouse model of pulmonary artery intimal sarcoma (2012)
  • Author(s): Jujo T, Sakao S, Kantake M, Maruoka M, Tanabe N, Kasahara Y, Kurosu K, Masuda M, Harigaya K, Tatsumi K
  • Journal Title: Int J Oncol Volume: 41(2) Pages: 701-11
  • Peer Reviewed
• [Journal Article] Interleukin 6 mediates production of interleukin 10 in metastatic melanoma (2012)
  • Author(s): Terai M, Eto M, Young GD, Berd D, Mastrangelo MJ, Tamura Y, Harigaya K, Sato T
  • Journal Title: Cancer Immunol Immunother Volume: 61 Pages: 145-55
  • Peer Reviewed
• [Journal Article] Fragmented hyaluronan is an autocrine chemokinetic motility factor supported by theHAS2-HYAL2/CD44 system on the plasma membrane (2011)
  • Author(s): Saito T, Kawana H, Azuma K,Toyoda,A,Fujita H, Kitagawa M, Harigaya K
  • Journal Title: Int J Oncol Volume: 39(5) Pages: 1311-20
  • Peer Reviewed
• [Journal Article] Overexpression of human ortholog of mammalian enabled (hMena) is associated with the expression of mutant p53 protein in human breast cancers (2011)
  • Author(s): Toyoda A, Yokota A, Saito T, Kawana H, Higashi M, Suzuki Y, Tanaka T, Kitagawa M, Harigaya K
  • Journal Title: Int J Oncol Volume: 38(1) Pages: 89-96
  • Peer Reviewed
• [Journal Article] Mastermind-like 1 (MamL1) andmastermind-like 3 (MamL3) are essential forNotch signaling in vivo (2011)
  • Author(s): Oyama T, Harigaya K, Sasaki N, Okamura Y, Kokubo H, Saga Y, Hozumi K, Suganami A, Tamura Y, Nagase T, Koga H, Nishimura M, Sakamoto R, Sato M, Yoshida N, Kitagawa M
  • Journal Title: Development Volume: 138 Pages: 5235-46
  • Peer Reviewed
• [Journal Article] Visualization of the Activity of Rac1Small GTPase in a Cell (2010)
  • Author(s): Higashi M, Yu J, Tsuchiya H, Saito T, Oyama T, Kawana H, Kitagawa M, Tamaru J, Harigaya K
  • Journal Title: Acta Histochem Cytochem Volume: 43(6) Pages: 163-8
  • Peer Reviewed
• [Journal Article] Fibroblasts associated with cancer cells keep enhanced migration activity after separation from cancer cells: a novel character of tumor educated fibroblasts (2010)
  • Author(s): Ishii G, Hashimoto H, Asada K, Ito T, Hoshino A, Fujii S, Kojima M, Kuwata T, Harigaya K, Nagai K, Ushijima T, Ochiai A
  • Journal Title: Int J Oncol Volume: 37(2) Pages: 317-25
  • Peer Reviewed
• [Journal Article] Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells (2010)
  • Author(s): Watarai H, Fujii S, Yamada D, Rybouchkin A, Sakata S, Nagata Y, Iida-Kobayashi M, Sekine-Kondo E, Shimizu K, Shozaki Y,Sharif J, Matsuda M, Mochiduki S, Hasegawa T, Kitahara G, Endo TA, Toyoda T, Ohara O, Harigaya K, Koseki H, Taniguchi M
  • Journal Title: J Clin Invest Volume: 120(7) Pages: 2610-8
  • Peer Reviewed
• [Journal Article] Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex (2010)
  • Author(s): Ishitani T, Hirao T, Suzuki M, Isoda M, Ishitani S, Harigaya K, Kitagawa M, Matsumoto K, Itoh M
  • Journal Title: Nat Cell Biol Volume: 12(3) Pages: 278-85
  • Peer Reviewed
• [Presentation] Switching of CD44 and hMena mRNA splice variants between the intramucosal lesion and invasive front of early stage human colorectal carcinoma (pT1), and their relationship to the expression of cancer stem cell markers and clinico- pathological features (2013)
  • Author(s): Yoshida H, Toyoda A, Tanaka N, Masuda W,Kitagawa M, Suzuki Y, Harigaya K
  • Organizer: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 280
  • Year and Date: 20130406-10
• [Presentation] HAS2-Hyal2/CD44 system supports spontaneous random cell movement of human cancer cells in an autocrine mechanism (2011)
  • Author(s): Saito T, Kawana H, Azuma K, Toyoda A, Fujita H, Kitagawa M, HarigayaK
  • Organizer: Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2011-01-23
• [Presentation] Fragmented hyalu- ronan is an autocrine chemokinetic motility factor supported by HAS2 -CD44/hyaluronidase-2 system on the plasma membrane (2010)
  • Author(s): Harigaya K
  • Organizer: 15th World Congress on Advances in Oncology
  • Place of Presentation: Loutaraki, Greece. (Invited Speaker)
  • Year and Date: 2010-10-08
• [Presentation] CD44 suppresses Toll-like receptor signaling (2010)
  • Author(s): Harigaya K
  • Organizer: 8th International Conference on Hyaluronan Science
  • Place of Presentation: Kyoto (Invited Speaker)
  • Year and Date: 2010-06-10