Abstract 5336: Targeting glioma growth and invasiveness by microRNA-1.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Median survival is about 14 months, even with the most effective regimen of surgery followed by radiation and chemotherapy. GBM is characterized by the hallmarks of cellular heterogeneity, rapid proliferation, angiogenesis and extensive invasion. The dual feature of high proliferation and infiltration constitutes the major challenge for glioma therapy, as even extensive resection of the primary tumor mass leaves a significant number of tumor cells in the brain and leads to almost unavoidable recurrence. Despite abundance of data concerning glioma growth/angiogenesis, the mechanisms underlying the regulation of glioma cell motility and invasiveness are comparatively poorly understood. Established anti-glioma therapeutical modalities (radiation, chemotherapy) target preferentially rapidly proliferating rather than infiltrating glioma cells. Moreover invading cells are resistant to conventional therapies, and anti-angiogenic treatment was shown to induce invasiveness. Thus novel therapies aiming at blockade of glioma invasion, while curbing their proliferative potential are needed. MicroRNAs (miRs) are small, single stranded, non-coding RNAs that act as key regulators of gene expression, by reducing translation of target mRNAs with partial complementarity in their 3′UTRs. MiRs deregulation is a general feature of cancer, including GBM, and was associated with tumor suppressor and oncogenic activities. A number of studies have identified critical roles for miRs in the regulation of tumor cell invasion, migration and metastasis. In this study we report that miR-1 is down-regulated in glioma patients (relatively to adjacent tissue) and that it is down-regulated in migrating glioma cells in vitro (relatively to non-migrating glioma cells). Its forced expression reduces glioma cell growth and angiogenesis in vivo. MiR-1 inhibits migration in vitro and invasiveness in vivo. Additionally, we demonstrated impaired cell-cell adhesion and aggregation in glioma cells expressing miR-1. We identified Annexin A2, recognized oncogene in glioma, as a direct target of miR-1. Annexin A2 is up-regulated in various tumor types, including glioma. In vivo studies revealed a critical role for Annexin A2 in driving glioma growth, angiogenesis, progression and invasion. Our results show that the effects of miR-1 on glioma cells are consistent with Annexin A2 down-regulation, including a reduction in glioma cell proliferation and invasiveness, and re-expression of Annexin A2 rescues the effect of miR-1 expression. When glioma cells stably expressing miR-1 were injected intracranially, we observed significantly improved survival when compared to control cells. Our results suggest that miR-1 inhibits simultaneously glioma growth and invasiveness in vivo and as such may be a candidate for the therapeutic targeting of glioma cells. Citation Format: Jakub A. Godlewski, Agnieszka Bronisz, Yan Wang, E. Antonio Chiocca. Targeting glioma growth and invasiveness by microRNA-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5336. doi:10.1158/1538-7445.AM2013-5336