RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop

// Nis David Giladi 1 , Amotz Ziv-Av 1 , Hae Kyung Lee 2 , Susan Finniss 2 , Simona Cazacu 2 , Cunli Xiang 2 , Hiba Waldman Ben-Asher 1 , Ana deCarvalho 2 , Tom Mikkelsen 2 , Laila Poisson 3 , Chaya Brodie 1, 2 1 Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel 2 Department of Neurosurgery, Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA 3 Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA Correspondence to: Chaya Brodie, e-mail: cbrodie1@hfhs.org Keywords: glioblastoma, glioma stem cells, RTVP-1, IL-6, mesenchymal transformation Received: March 26, 2015      Accepted: July 06, 2015      Published: July 18, 2015 ABSTRACT 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.