The semaphorin 3A/neuropilin-1 pathway promotes clonogenic growth of glioblastoma via activation of TGF-β signaling.

Autor:	Jeon HM; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Shin YJ; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea., Lee J; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.; Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, South Korea., Chang N; Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, South Korea., Woo DH; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Lee WJ; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Nguyen D; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA., Kang W; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea., Cho HJ; Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, South Korea., Yang H; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea., Lee JK; Department of Biomedical Sciences and Department of Anatomy and Cell Biology, Seoul National University, College of Medicine, Seoul, South Korea., Sa JK; Department of Biomedical Sciences, Korea University, College of Medicine, Seoul, South Korea., Lee Y; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea., Kim DG; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea., Purow BW; Department of Neurology, University of Virginia, Charlottesville, Virginia, USA., Yoon Y; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.; Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, South Korea., Nam DH; Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea.; Graduate School of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, South Korea., Lee J; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2023 Nov 08; Vol. 8 (21). Date of Electronic Publication: 2023 Nov 08.
DOI:	10.1172/jci.insight.167049
Abstrakt:	Glioblastoma (GBM) is the most lethal brain cancer with a dismal prognosis. Stem-like GBM cells (GSCs) are a major driver of GBM propagation and recurrence; thus, understanding the molecular mechanisms that promote GSCs may lead to effective therapeutic approaches. Through in vitro clonogenic growth-based assays, we determined mitogenic activities of the ligand molecules that are implicated in neural development. We have identified that semaphorin 3A (Sema3A), originally known as an axon guidance molecule in the CNS, promotes clonogenic growth of GBM cells but not normal neural progenitor cells (NPCs). Mechanistically, Sema3A binds to its receptor neuropilin-1 (NRP1) and facilitates an interaction between NRP1 and TGF-β receptor 1 (TGF-βR1), which in turn leads to activation of canonical TGF-β signaling in both GSCs and NPCs. TGF-β signaling enhances self-renewal and survival of GBM tumors through induction of key stem cell factors, but it evokes cytostatic responses in NPCs. Blockage of the Sema3A/NRP1 axis via shRNA-mediated knockdown of Sema3A or NRP1 impeded clonogenic growth and TGF-β pathway activity in GSCs and inhibited tumor growth in vivo. Taken together, these findings suggest that the Sema3A/NRP1/TGF-βR1 signaling axis is a critical regulator of GSC propagation and a potential therapeutic target for GBM.
Databáze:	MEDLINE
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