Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma

Jun Hee Hong, Sangjo Kang, Jason K. Sa, Gunwoo Park, Young Taek Oh, Tae Hoon Kim, Jinlong Yin, Sung Soo Kim, Fulvio D'Angelo, Harim Koo, Yeonhee You, Saewhan Park, Hyung Joon Kwon, Chan Il Kim, Haseo Ryu, Weiwei Lin, Eun Jung Park, Youn Jae Kim, Myung Jin Park, Hyunggee KimMi Suk Kim, Seok Chung, Chul Kee Park, Sung Hye Park, Yun Hee Kang, Jong Heon Kim, Hideyuki Saya, Ichiro Nakano, Ho Shin Gwak, Heon Yoo, Jeongwu Lee, Eun Mi Hur, Bingyang Shi, Do Hyun Nam, Antonio Iavarone, Seung Hoon Lee, Jong Bae Park

研究成果: Article査読

抄録

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

本文言語English
ページ(範囲)636-654
ページ数19
ジャーナルBrain : a journal of neurology
144
2
DOI
出版ステータスPublished - 2021 3 3

ASJC Scopus subject areas

  • 臨床神経学

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