CD44-targetted therapy for CD44-high expressing tumors by ultra-low-molecular-weight hyaluronan

2015 Fiscal Year Final Research Report

• Project/Area Number: 25461585
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Yamanashi
• Principal Investigator: SUGITA Kanji 山梨大学, 総合研究部, 教授 (60138055)
• Co-Investigator(Renkei-kenkyūsha): INUKAI Takeshi 山梨大学, 総合研究部, 准教授 (30293450) ; GOI Kumiko 山梨大学, 総合研究部, 講師 (70324192) ; OSHIRO Hiroko 山梨大学, 総合研究部, 助教 (50377537)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 超低分子量ヒアルロン酸 / 白血病 / CD44 / 細胞死 / ネクローシス

Outline of Final Research Achievements

We investigated the biological effects of ultra-low-molecular-weight (ULMW)-HA on MLL+ALL cell lines with high surface expression of CD44, and found that the addition of ULMW-HA strongly suppressed thymidine uptakes. The cell line almost lacking surface CD44 expression established by genome editing using CRISPR/Cas9 system showed no suppression, demonstrating an essential role of surface CD44 expression for ULMW-HA-triggered inhibition of thymidine uptake. This inhibition was not due to cell cycle arrest but due to induction of cell death. The cell death was neither blocked by pan-caspase inhibitor Z-VAD-FMK nor autophagy inhibitor 3-methyladenine, but was completely blocked by necrosis inhibitor necrostatin-1. ULMW-HA-triggered necrotic cell death was further supported by morphological changes on transmission electron microscopy. Elevation of intracellular reactive oxygen species production after ULMW-HA stimulation suggested a role for inducting this necrotic cell death.

Free Research Field

小児科