RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop.
Glioblastomas (GBMs), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. We explored the role of RTVP-1, a glioma-associated protein that promotes glioma cell migration, in the mesenchymal transformation of GBM. Analysis of The Cancer Genome Atlas (TCGA) demonstrated that RTVP-1 expression was higher in mesenchymal GBM and predicted tumor recurrence and poor clinical outcome. ChiP analysis revealed that the RTVP-1 promoter binds STAT3 and C/EBPβ, two master transcription factors that regulate mesenchymal transformation of GBM. In addition, IL-6 induced RTVP-1 expression in a STAT3-dependent manner. RTVP-1 increased the migration and mesenchymal transformation of glioma cells. Similarly, overexpression of RTVP-1 in human neural stem cells induced mesenchymal differentiation, whereas silencing of RTVP-1 in glioma stem cells (GSCs) decreased the mesenchymal transformation and stemness of these cells. Silencing of RTVP-1 also increased the survival of mice bearing GSC-derived xenografts. Using gene array analysis of RTVP-1 silenced glioma cells we identified IL-6 as a mediator of RTVP-1 effects on the mesenchymal transformation and migration of GSCs, therefore acting in a positive feedback loop by upregulating RTVP-1 expression via the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM.
Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Nis David
ND
Giladi
Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Amotz
A
Ziv-Av
Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Hae Kyung
HK
Lee
Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Susan
S
Finniss
Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Simona
S
Cazacu
Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Cunli
C
Xiang
Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Hiba
H
Waldman Ben-Asher
Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Ana
A
deCarvalho
Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Tom
T
Mikkelsen
Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
Laila
L
Poisson
Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.|Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA.
Chaya
C
Brodie
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection
C094538:GLIPR1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
IL-6; RTVP-1; glioblastoma; glioma stem cells; mesenchymal transformation