Abstract 585: WIF1 re-expression in glioblastoma impairs migration through downregulation of the lncRNA MALAT1

Abstract

Abstract Glioblastoma is the most aggressive form of human glioma. Despite progress in brain tumor therapy the prognosis remains dismal with a median survival of 15 months. We have recently shown that WIF1, an inhibitor of the WNT pathway, is downregulated in glioblastoma where it functions as strong tumor suppressor gene. Indeed, WIF1 re-expression impairs cell growth, cell migration, induces a senescence-like phenotype, and inhibits tumorigenicity in several orthotopic xenograft models. To analyse the molecular mechanisms underlying the tumor suppressive functions of WIF1 we developed a TET-on inducible system. Gene expression profiling following WIF1 induction revealed several interesting candidate genes validated in additional cell lines. The gene with strongest downregulation in WIF1-induced cells was MALAT1. MALAT1 is a long non-coding RNA that has been associated with tumor aggressiveness and invasion. Hence, MALAT1 is a plausible candidate, and its downregulation may contribute to the attenuation of malignancy seen in WIF1 expressing cells. Preliminary results show that the expression of a MALAT1 specific short-hairpin drastically reduces the infiltrative capability of glioblastoma cells. Analysis of gene xpression profiles revealed that MALAT1 is overexpressed in glioblastoma as compared to non-tumoral brain. These observations suggest that MALAT1 may contribute to the aggressive phenotype of glioblastoma. Experiments to test the effect of downregulation of MALAT1 in vivo are now ongoing. The poor prognosis is partially due to the extremely high capability of glioblastoma cells to migrate and to invade the surrounding brain structures, impairing complete surgical resection, hence leading inevitably to recurrence. This provides the rational to further investigate implications of MALAT1 in migration. Understanding the mechanisms of high invasive properties may indeed lead to the identification of new targets for therapy. Citation Format: Irene Vassallo, Marie-France Hamou, Monika E. Hegi. WIF1 re-expression in glioblastoma impairs migration through downregulation of the lncRNA MALAT1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2014-585