Non-coding RNAs have been implicated as master regulators of several biological processes, their expression being strictly regulated under physiological conditions. In recent years, particularly in the last decade, substantial effort has been made to investigate the function of ncRNAs in several human diseases, including cancer. The aim of this review is to guide the reader through important aspects of miRNA and lncRNA biology, focusing on the molecular mechanism associated with glioblastoma onset/progression.
For decades, it has been believed that the central dogma of Molecular Biology (DNA → mRNA → Protein) was unidirectional, with all the complex cellular processes of an organism being solely due to the structural and catalytic functions of proteins . Currently, it is widely accepted that this biological complexity is derived from the non-coding DNA portion of the genome, which was once thought of as ‘junk DNA’ (non-codifying DNA). Non-coding RNA (ncRNA) is a class of RNAs which has no potential for translation into proteins. The DNA sequence from which a functional ncRNA is transcribed is often called an RNA gene. The number of ncRNAs within the human genome is unknown; however, massive expansion of global transcriptome datasets from genomics consortia have been demonstrating that most of the human genome is transcribed into non-coding RNAs . According to the Encyclopedia of DNA elements (ENCODE) project, approximately 75% of the human genome is actively transcribed into ncRNAs , only 2% of which code for known protein-coding genes . Importantly, ncRNAs have been revealed to be functional and to form complex regulatory networks associated with several biological processes. Disruption of key components of these networks leads to deregulated cell function and contributes to human disease states, including cancer .
Glioblastoma is the most aggressive type of brain cancer in adults, accounting for about half of all primary brain tumors . Despite the multimodal treatment procedure, which consists of maximal resection followed by radiotherapy and chemotherapy, the overall survival rate remains only 12–15 months, highlighting the urgent need for more effective targeted therapy .
New insights into the molecular subtypes of diffuse gliomas have led to unprecedented discoveries of potential prognostic and predictive markers . The latest classification system announced by the World Health Organization (WHO)  combines the classical histomorphological analysis with molecular genetic tests, allowing more precise diagnosis and guidance for therapeutic interventions . Further studies in this direction should provide the basis for the development of novel therapeutic strategies targeting unique molecular signatures for patient-tailored treatment.
Non-coding RNAs have increasingly been described as biomarkers of various human diseases  and/or suggested as therapeutic targets . In this context, the aim of this article is to review the exciting progress towards elucidating the multifunctional facet of ncRNAs, with special focus on glioblastoma-associated miRNAs and lncRNAs. Finally, we also discuss the limitations and obstacles to translate these findings into the clinical practice.
LncRNAs play a central role in transcriptional and post-transcriptional regulation of protein-coding genes and may be categorized into different archetypes, such as: ceRNAs/miRNA sponges, guides, scaffolds, or enhancers. MiRNAs act at the post-transcriptional level by mRNA cleavage, blocking mRNA translation and/or mRNA stability.
LncRNAs and miRNAs are critical ncRNAs inserted in a complex regulatory network, with abnormal expression of these molecules having a direct impact on several aspects of gliomagenesis.
In conclusion, the lncRNA–miRNA–mRNA crosstalk represents a master regulatory key for maintenance of cellular homeostasis. The lncRNA-miRNA co-expression network provides an extra layer of complexity into how these molecules can contribute to glioblastoma onset, progression, and maintenance. This complex network of lncRNA-miRNA interactions is a prominent field of research, which may reveal potential therapeutic options for patient-tailored treatment.