SCIDOT-27. TGFβ SIGNALING-INDUCED miRNA PARTICIPATES IN AUTOPHAGIC REGULATION BY TARGETING PRAS40 IN MESENCHYMAL SUBTYPE OF GLIOBLASTOMA

Abstract

Abstract Mesenchymal subtype of glioblastoma (mesGBM) is a refractory disease condition characterized by therapeutic failure and tumor recurrence, and for the past decade, no treatment option has improved the dismal prognosis of this disease. In Cancer Genome Atlas (TCGA) GBM datasets, two of the 840 transcriptomic signature genes for GBM subtyping, TGFβ1 and TGFβ receptor type II (TβRII), were exclusively upregulated in mesGBM, indicating hyperactive TGFβ signaling. In the present study, dysregulated microRNAs (miRNAs) were identified after LY2109761 (a TβRI/II inhibitor) treatment in a mesGBM-derived cell line. Importantly, several novel miRNAs that may be missing pieces of the puzzle of TGFβ signaling-mediated pathogenesis in mesGBM were identified. Novel_miR26/56/93/97/119 were validated by quantitative PCR to correlate with TGFβ signaling activity, and novel_miR56 was selected as a promising candidate for further functional verification. A proline-rich akt substrate of 40 kDa (PRAS40), which regulates autophagy initiation by targeting mTORC1, was confirmed to be a functional target of novel_miR56. Autophagy plays dichotomous roles in the determination of GBM cell fate, and in this study, TGFβ signaling-induced novel_miR56 seemed to inhibit autophagic activity in GBM and its mesenchymal subtype, resulting in the maintenance of proliferative capability. The pro-survival effect of novel_miR56 can be impeded by intentionally downregulating its expression both in vivo and in vitro. In summary, we provide novel insight into TGFβ signaling-mediated pathogenesis and targets for the development of novel therapeutic interventions for mesGBM.