MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours

Abstract

The development of childhood solid tumours is tied to early developmental processes. These tumours may be complex and heterogeneous, and elucidating the aberrant mechanisms that alter the early embryonic environment and lead to disease is essential to our understanding of how these tumours function. MicroRNAs (miRNAs) are vital regulators of gene expression at all stages of development, and their crosstalk via developmental signalling pathways is essential for orchestrating regulatory control in processes such as proliferation, differentiation and apoptosis of cells. Oncogenesis, from aberrant miRNA expression, can occur through amplification and overexpression of oncogenic miRNAs (oncomiRs), genetic loss of tumour suppressor miRNAs, and global miRNA reduction from genetic and epigenetic alterations in the components regulating miRNA biogenesis. While few driver mutations have been identified in many of these types of tumours, abnormal miRNA expression has been found in a number of childhood solid tumours compared to normal tissue. An exploration of the network of key developmental pathways and interacting miRNAs may provide insight into the development of childhood solid malignancies and how key regulators are affected. Here we present a comprehensive introduction to the roles and implications of miRNAs in normal early development and childhood solid tumours, highlighting several tumours in depth, including embryonal brain tumours, neuroblastoma, osteosarcoma, Wilms tumour, and hepatoblastoma. In light of recent literature describing newer classifications and subtyping of tumours based on miRNA profiling, we discuss commonly identified miRNAs, clusters or families associated with several solid tumours and future directions for improving therapeutic approaches.

Keywords: Childhood solid tumours; Early development; Hepatoblastoma; Medulloblastoma; MicroRNAs; Neuroblastoma; Osteosarcoma; Wilms Tumour.

Fig. 1

Proposed schematic of early developmental processes linking key signalling pathways and miRNA expression. a The developmental signalling pathway expression in early stages of development (Carnegie stages 1–9), and the miRNAs demonstrated to regulate these pathways during these stages. b Carnegie stages 10–17, representing further development and miRNAs ubiquitously expressed in all tissues (except heart and vessels). The three germ layers are represented and their associated body systems and organs are discussed in a cancer context in this review (kidney; WT, bone; OS, Neural crest; NB, brain; embryonal brain tumours, liver; HB). Additionally miRNAs associated with each organ/body system are presented

Fig. 2

The mechanisms by which alteration of normal miRNA profiles can occur, leading to aberrant miRNA profiles in childhood solid tumours. Examples of aberrant expression and disrupted miRNA biogenesis are illustrated and are supported by validation in the literature. a Disruptions to miRNA genes, resulting in upregulation of oncogenic miRNAs or downregulation, or complete loss of expression (tumour suppressor miRNAs). b Components of the miRNA biogenesis pathway that can be altered, affecting production of mature functioning miRNAs. c Events which alter the target mRNA and affect the ability of the mature miRNA to bind