RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop
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Nis David Giladi1, Amotz Ziv-Av1, Hae Kyung Lee2, Susan Finniss2, Simona Cazacu2, Cunli Xiang2, Hiba Waldman Ben-Asher1, Ana deCarvalho2, Tom Mikkelsen2, Laila Poisson3, Chaya Brodie1,2
1Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
2Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA
3Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA
Chaya Brodie, e-mail: firstname.lastname@example.org
Keywords: glioblastoma, glioma stem cells, RTVP-1, IL-6, mesenchymal transformation
Received: March 26, 2015 Accepted: July 06, 2015 Published: July 18, 2015
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.
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