MiRNAs 484 and 210 Regulate Pax-5 Expression and Function in Breast Cancer Cells.

Abstract

Recent studies have enabled the identification of important factors regulating cancer progression, such as Pax-5. This transcription factor has consistently been associated to B cell cancer lesions and more recently solid tumors including breast carcinoma. Although Pax-5 downstream activity is relatively well characterized, aberrant Pax-5 expression in a cancer specific context is poorly understood. To investigate the regulation of Pax-5 expression, we turned to micro-RNAs (miRNAs), small non-coding RNA molecules that regulate key biological processes. Extensive studies show that miRNA deregulation is prevalent in cancer lesions. In this study, we aim to elucidate a causal link between differentially expressed miRNAs in cancer cells and their putative targeting of Pax-5-dependent cancer processes. Bioinformatics indicate that miRNAs 484 and 210 are aberrantly expressed in breast cancer and predicted to target Pax-5 mRNA. Through conditional modulation of these miRNAs in breast cancer cells, we demonstrate that miRNA-484 and 210 inhibit Pax-5 expression and regulate Pax-5-associated cancer processes. In validation, we show that these effects are likely caused by direct miRNA/mRNA interaction which are reversible by Pax-5 recombinant expression. Interestingly, miRNAs 484 and 210, which are both overexpressed in clinical tumor samples, are also modulated during epithelial to mesenchymal transitioning (EMT) and hypoxia which correlate inversely to Pax-5 expression. This is the first study demonstrating the regulation of Pax-5 expression and function by non-coding RNAs. These findings will help us better understand Pax-5 aberrant expression within cancer, creating the possibility for more efficient diagnosis and treatments for cancer patients.