한빛사 논문
Jinlong Yin1,2,3,13, Sung Soo Kim2,3,13, Eunji Choi4,13, Young Taek Oh3,5,6,13, Weiwei Lin3,
Tae-Hoon Kim3, Jason K. Sa5,7, Jun Hee Hong3, Se Hwan Park2, Hyung Joon Kwon4, Xiong Jin8,12, Yeonhee You2, Ji Hye Kim9, Hyunggee Kim8, Jaekyoung Son9, Jeongwu Lee10, Do-Hyun Nam5, Kui Son Choi4, Bingyang Shi1, Ho-Shin Gwak4, Heon Yoo2,3, Antonio Iavarone6,*, Jong Heon Kim2,11,* & Jong Bae Park2,3,*
1Henan and Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China.
2Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
3Rare Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
4Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
5Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
6Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA. 7Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea. 8Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
9Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
10Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
11Division of Cancer Biology, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
12Present address: Laboratory of Stem Cells, NEXELCo., Ltd., Seoul, Republic of Korea.
13These authors contributed equally: Jinlong Yin, Eunji Choi, Sung Soo Kim, Young Taek Oh.
*Corresponding author
Abstract
The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
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