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

Authors

Nis D. Giladi
Amotz Ziv-Av
Hae-Kyung Lee, Henry Ford HealthFollow
Susan Finniss, Henry Ford Health
Simona Cazacu, Henry Ford HealthFollow
Cunli Xiang, Henry Ford HealthFollow
Hiba Waldman Ben-Asher
Ana C. de Carvalho, Henry Ford HealthFollow
Tom Mikkelsen, Henry Ford HealthFollow
Laila M. Poisson, Henry Ford Health Sciences CenterFollow
Chaya Brodie, Henry Ford HealthFollow

Recommended Citation

Giladi ND, Ziv-Av A, Lee HK, Finniss S, Cazacu S, Xiang C, Ben-Asher HW, deCarvalho A, Mikkelsen T, Poisson L, and Brodie C. RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop. Oncotarget 2015; 6(26):22680-22697.

Document Type

Article

Publication Date

9-8-2015

Publication Title

Oncotarget

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.

Comments

© authors, Creative Commons Attribution License

Medical Subject Headings

Animals; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Glioma; Heterografts; Humans; Interleukin-6; Mice; Mice, Nude; Neoplasm Proteins; Nerve Tissue Proteins; STAT3 Transcription Factor; Signal Transduction; Transcriptional Activation; Transfection

PubMed ID

26267319

Volume

6

Issue

26

First Page

22680

Last Page

22697