Drug resistance and the functional role of microRNAs in neuroblastoma

Abstract

Neuroblastoma is the most common solid tumor in infants. Most of the children diagnosed above one year of age, shows metastatic disease and poor prognosis. Chemotherapy is one of the principle mode of treatment. However, resistance to drug represent a major clinical obstacle for the effective treatment of cancer. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression, and dysregulation of miRNAs is commonly observed in different cancer types. Recently, miRNAs are shown to modulate drug resistance; however, the role of miRNAs in drug resistant neuroblastoma is limited and poorly understood. <p>

<p>This study is focused on the identification and the functional role of miRNAs in drug resistant neuroblastoma. In paper-I, we performed miRNA-profiling study to elucidate miRNAs that are expressed in the cell lines isolated from the same patients before (parental) and after chemotherapy (resistant). We observed differential expression of 42-miRNAs (34-downregulated and 8-upregulated) across parental and resistant cells. Interestingly, <i>miR-376c-3p</i> and <i>miR-323a-3p</i> were markedly downregulated in resistant cell lines and in a cohort of 226-primary neuroblastoma tumors. In Paper-II and -III, over-expression studies showed that <i>miR-376c-3p</i> and </i>miR-323a-3p</i> targets the oncogenes <i>CCND1</i> and <i>STAT3</i>, respectively and induce G1-cell cycle arrest and apoptosis in neuroblastoma cells.