Identifying MicroRNAs as Potential Therapeutic Targets in Retinoblastoma

Abstract

Purpose: : Retinoblastoma, the most common pediatric cancer of the eye, is a devastating and sometimes fatal pediatric cancer. Within the United States, the majority of retinoblastoma patients are diagnosed before their 2nd birthday, and many lose their sight due to this disease. Approximately 75% of the retinoblastoma patients in the United States have unilateral disease, and treatment for many unilateral patients with advanced disease involves enucleation (removal of the eye). Therefore, new more effective targeted therapies for retinoblastoma could save a child’s quality of life by preserving their sight. Outside of the United States, advanced retinoblastoma is an even greater clinical challenge in low-income countries, where the mortality rate among children diagnosed with advanced retinoblastoma is as high as 70%. Currently, the chemotherapeutic treatments for retinoblastoma involve the use of broad-based drugs. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. MicroRNAs, short noncoding RNA transcripts that can regulate the expression of target genes, are known to affect the progression of many different tumor types. MicroRNAs (miRNAs) are also ideal therapeutic targets because they are amenable to therapeutic manipulation. Therefore, the purpose of our study is to identify differentially expressed miRNAs that may serve as potential targets for therapeutic intervention.

Methods: : To identify miRNAs associated with retinoblastoma progression, we have conducted miRNA profiling studies using a Real-Time PCR based miRNA array and Real-Time PCR validation assays on late-stage human retinoblastoma tumors.

Results: : Our analysis has led to the identification of 41 differentially expressed miRNAs (p<0.05) in retinoblastoma as compared to normal human retina. We have validated the downregulation of 5 of these miRNAs in a cohort of primary retinoblastoma tumors.

Conclusions: : These miRNAs could serve as potential therapeutic targets for retinoblastoma due to their known involvement in viability, proliferation, cell cycle regulation, and apoptosis in other tumor types. This is an essential step in the discovery of miRNAs associated with retinoblastoma progression, and in the identification of potential therapeutic targets for this disease.

Keywords: retinoblastoma