MP72-06 THE LONG NON-CODING RNA SNHG18 PROMOTES PPARγ FUNCTION AND “LUMINAL” GENE EXPRESSION IN MUSCLE-INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVES: Long non-coding RNAs (lncRNAs) are emerging as important drivers of disease progression, and have been shown to modulate gene expression at several levels. Unfortunately, the molecular functions of a majority of lncRNAs identified are still poorly understood. While recent studies have identified subtypes of muscle-invasive bladder cancer (MIBC) at the mRNA level, the overall goal of this study is to obtain a deeper understanding of the lncRNAs that contribute to the molecular mechanisms that underlie the intrinsic subtypes of MIBC. METHODS: In this study, we utilized TCGA’s RNA-sequencing data to extract whole genome lncRNA expression from 211 MIBCs. Unsupervised consensus clustering was utilized to identify subtypes based on lncRNA expression profiles, and differential expression analysis was performed in the R statistical programming environment. To further study the lncRNAs associated with the luminal subtype, cell lines were exposed to rosiglitazone, a PPARg agonist, and RNA-sequencing was performed. PPARg associated lncRNA candidates were validated in an independent cohort using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Consensus clustering of lncRNA expression identified two intrinsic subtypes of MIBCs, which were synonymous with the intrinsic basal and luminal subtypes recently discovered through mRNA expression profiling. Previous work has shown that PPARg is amplified in approximately 15% of luminal MIBCs, and luminal MIBCs are enriched with an activePPARgmRNAexpression signature. In this study, lncRNAs up-regulated after exposure to rosiglitazone were highly expressed in luminal MIBCs, as confirmed by gene set enrichment analysis (GSEA). Differential expression analysis revealed SNHG18 to be up-regulated after PPARg activation, and to be highly expressed in luminal MIBCs. RNA immunoprecipitation studies confirmed that SNHG18 is directly bound by PPARg, and subsequent knockdown of SNHG18 resulted in decreased expression of several luminal PPARg target genes including uroplakins and fibroblast growth factor receptor-3 (FGFR3). CONCLUSIONS: Currently, FGFR3 is an important therapeutic target in MIBCs with activating mutations occurring in approximately 17% of cases. Overall, we have identified a novel lncRNA, SNHG18, to be a co-activator of PPARg that controls downstream expression of FGFR3. The results suggest that SNHG18 could potentially serve as a predictive biomarker, or as a possible drug target to increase the efficiency of FGFR3 targeted therapies.