방사선의학 웹진

바로가기  >

Abstract

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NFκB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radio-resistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. 

Author information

Yin J1, Oh YT2, Kim JY3, Kim SS1, Choi E4, Kim TH2, Hong JH2, Chang N5, Cho HJ6, Sa JK7, Kim JC3, Kwon HJ4, Park S1, Lin W8, Nakano I9, Gwak HS10, Yoo H11, Lee SH12, Lee J13, Kim JH14, Kim SY15, Nam DH16, Park MJ17, Park JB18.​

1Department of System Cancer Science, National Cancer Center.2Specific Organs Cancer Branch, National Cancer Center.3Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences.4Department of Cancer Control and Policy, National Cancer Center.5Department of Neurosurgery, Samsung Medical Center.6Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University School of Medicine.7Neurosurgery, Samsung Medical Center.8national cancer center.9Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham.10Neuro-Oncology Clinic, National Cancer Center.11Neuro-Oncology Clinic, National Cancer Center Korea.12Department of neuro-oncology, Eulgi university school of medicine.13Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute.14Carcinogenesis Branch, National Cancer Center.15Cancer Cell & Molecular Biology Branch, National Cancer Center.16Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine.17Division of Radiation Cancer Research, KIRAMS.18Department of System Cancer Science, National Cancer Center jbp@ncc.re.kr.