miRNA dysregulation in cancer: towards a mechanistic understanding

It is now well known that gene expression is intricately regulated inside each cell especially in mammals. There are multiple layers of gene regulation active inside a cell at a given point of time. Gene expression is regulated post-transcriptionally by microRNAs and other factors. Mechanistically, microRNAs are known to bind to the 3' UTR of mRNAs and cause repression of gene expression and the number of known microRNAs continues to increase every day. Dysregulated microRNA signatures in different types of cancer are being uncovered consistently implying their importance in cellular homeostasis. However when studied in isolation in mouse models, clear-cut cellular and molecular mechanisms have been described only for a select few microRNAs. What is the reason behind this discrepancy? Are microRNAs small players in gene regulation helping only to fine tune gene expression? Or are their roles tissue and cell type-specific with single-cell level effects on mRNA expression and microRNA threshold levels? Or does it all come down to the technical limitations of high-throughput techniques, resulting in false positive results? In this review, we will assess the challenges facing the field and potential avenues for resolving the cellular and molecular mechanisms of these small but important regulators of gene expression.