Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.
Glioblastoma stem cells (GSC) express both radial glial cell and neural crest cell (NCC)-associated genes. We report that endothelin 3 (EDN3), an essential mitogen for NCC development and migration, is highly produced by GSCs. Serum-induced proliferative differentiation rapidly decreased EDN3 production and downregulated the expression of stemness-associated genes, and reciprocally, two glioblastoma markers, EDN1 and YKL-40 transcripts, were induced. Correspondingly, patient glioblastoma tissues express low levels of EDN3 mRNA and high levels of EDN1 and YKL-40 mRNA. Blocking EDN3/EDN receptor B (EDNRB) signaling by an EDNRB antagonist (BQ788), or EDN3 RNA interference (siRNA), leads to cell apoptosis and functional impairment of tumor sphere formation and cell spreading/migration in culture and loss of tumorigenic capacity in animals. Using exogenous EDN3 as the sole mitogen in culture does not support GSC propagation, but it can rescue GSCs from undergoing cell apoptosis. Molecular analysis by gene expression profiling revealed that most genes downregulated by EDN3/EDNRB blockade were those involved in cytoskeleton organization, pause of growth and differentiation, and DNA damage response, implicating the involvement of EDN3/EDNRB signaling in maintaining GSC migration, undifferentiation, and survival. These data suggest that autocrine EDN3/EDNRB signaling is essential for maintaining GSCs. Incorporating END3/EDNRB-targeted therapies into conventional cancer treatments may have clinical implication for the prevention of tumor recurrence.
Department of Surgery/Surgical Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
Yue
Y
Liu
Fei
F
Ye
Kazunari
K
Yamada
Jonathan L
JL
Tso
Yibei
Y
Zhang
David H
DH
Nguyen
Qinghua
Q
Dong
Horacio
H
Soto
Jinny
J
Choe
Anna
A
Dembo
Hayley
H
Wheeler
Ascia
A
Eskin
Ingrid
I
Schmid
William H
WH
Yong
Paul S
PS
Mischel
Timothy F
TF
Cloughesy
Harley I
HI
Kornblum
Stanley F
SF
Nelson
Linda M
LM
Liau
Cho-Lea
CL
Tso
D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D019334:Endothelin-3 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells; D009432:Neural Crest / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D034741:RNA, Small Interfering; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*
D019334:Endothelin-3; D034741:RNA, Small Interfering; D044023:Receptor, Endothelin B