Preliminary Research On MicroRNA Expression Profile Prognostic Value In Central Nervous System Hemangiopericytoma Recurrence

Hemangiopericytoma (HPC) is a rare type of mesenchymal tumor with localization in central nervous system and soft tissues anywhere in human body. According to the WHO Classification of Tumours of the Central Nervous System, HPC was difined as a mesenchymal, non-meningothelial tumour, WHO grade Ⅱ-Ⅲ, which accounted for 0.5% tumors of central nervous system with a high recurrence rate. However, the molecular pathogenic and malignancy mechanism of tumor occurrence is poorly developed, and is still calling for further studies on effective diagnostic and treatment strategies for this disease.MicroRNAs (miRNAs) are a class of 19 to 25 nucleotide (nt) length, endogenous, small, single-stranded noncoding RNA molecules which can regulate gene expression post- transcriptionally or bind to the 3’untranslated region (3’UTR) of the target mRNA to trigger mRNA degradation, thereby influence numerous processes, such as proliferation, cell cycle control, apoptosis, differentiation, migration and metabolism. Over than 2,000 human miRNAs (http://www.mirbase.org/) have been identified in the human genome so far and they are expressed in a tissue-specific manner. Each miRNA is of numerous target genes, whose expression is regulated by different mechanisms including transcription factor binding, epigenetic alterations, and chromosomal abnormalities. It is found that links between miRNAs and human diseases are extremely close. A large number of studies have shown that miRNAs play roles as tumor suppressors or oncogenes in cancers. Therefore, study on the miRNA expression profile of HPC could be a novel strategy for understanding pathophysiological process of HPC, and provide a fundament for the future research.Objective:Hemangiopericytomas of the central nervous system are often characterized by aggressive biological behavior and recurrent tumor growth. This topic seeks to carryout the HPC related analysis of miRNA expression profile by high-throughput miRNA microarray, and investigates whether miRNA expression profiles can predict clinical outcome of HPC patients.Methods:We retrospectively analysed miRNA expression profiles in 19 paraffin-embedded specimens of primary HPC from Huashan Hospital (Shanghai, China) and 6 specimens of normal dura. Using a 2006 probes microarray, we obtained differential miRNA expression profiles in HPC patients. Using permutation test and Cox regression analysis, we identified four miRNAs that potentially has to do with the prognosis of HPC patients. We used the Kaplan-Meier method to estimate correlations of the miRNA signature with progression-free survival (PFS) and overall survival (OS). Using quantitative RT-PCR, we obtained miRNA expressions in an enlarged scale, which contains 42 primary HPC patients treated from 2001-2008 in our hospital. Kaplan-Meier and multivariate Cox proportional hazard regression analyses were performed to assess whether miRNA expression could predict the outcome of HPC patients. Some bioinformatical tools such as PicTar、TagetScan、 miRanda、miRBase were also used to predict target genes.Results:166 miRNAs were found to exhibit significantly different expression profiles in HPC samples compared to normal dura samples, among which 108 were upregulated and 58 were downregulated. Four miRNAs (hsa-miR-1273e, hsa-miR-1972, hsa-miR-3934-3p and hsa-miR-4497) with predictive potential were founded by using permutation test and Cox regression analysis. qRT-PCR identified that low expression of has-miR-1273e correlated significantly with higher recurrence rates in HPC patients (p=0.034). Cox proportional hazard regression analysis revealed that has-miR-1273e expression level is an independent predictor of the tumor relapse (p=0.024). Bioinformatical analysis demonstrated that RBBP5, CTNND1, MAPK, RAP1A, NF2, RERG, RAB33B and BAG1 might be the target gene of has-miR-1273e.Conclusions:Our results suggest that the use of miRNA profiling has significant potential as an effective diagnostic and prognostic marker in HPC, and that has-miR-1273e may be of ability in predicting HPC patients’ outcomes.