By Giovanni Blandino

Recent studies have revealed that about 901X1 of the eukaryotic genome is transcribed. Interestingly, only 1-2% of these transcripts encode for proteins, the majority are transcribed as non-coding RNAs (ncRNAs).

During the past few years ncRNAs, previously thought as transcriptional junk, have become a research goldmine. The functions of ncRNAs are likely diverse, and their underlying mechanisms are just beginning to be understood. For sure ncRNAs are important regulatory molecules of many cellular processes in development and diseases, among which cancer, and have been identified as the key gene expression regulators.

The NCR group is mainly focused on three classes of ncRNA: microRNAs (miRNAs) long-non-coding RNAs (lncRNAs) and circular RNAs (circRNAs).

MiRNAs are small single-stranded molecules (20-24 nt) that derive from transcripts with distinctive hairpin structures. The hairpin is processed into mature miRNA by two endonucleases, Drosha and Dicer, and forms the RNA induced silencing complex (RISC). The miRNAs will pair with complementary sequences on target mRNAs transcripts through the 3’UTR, leading to gene silencing of the target.

LncRNAs are non-protein coding transcripts >200 nt in length that have been shown to control every level of the multi-level regulated gene expression pathway. For example, they are implicated in post-transcriptional gene regulation through controlling protein synthesis, RNA maturation and transport, the amount of available functional miRNAs, and in transcriptional gene silencing through regulating the chromatin structure.

CircRNAs are a large class of endogenous RNAs formed by exon skipping or back-splicing events as covalently closed loops, which are expressed abundantly in mammalian cells. CircRNAs can regulate transcription, RNA splicing and, as for lncRNAs, they can function as miRNA sponges.

The studies conducted by the NCR group are based on two principal approaches: a) one of more basic research approach that is intent to discovery the molecular mechanisms at the basis of rniRNAs, lnRNAs and circRNAs deregulation and functions in cancer cells; b) the other one is based on translational research approaches aimed to identify, by genome-wide screening, rniRNA, lncRNAs and circRNAs deregulated in tissue and liquid biopsies derived from cancer patients of our Institute, in way to discovery novel molecular biomarkers with clinical-prognostic impact and to develop innovative and more effective therapeutic approaches.

The research activity of NCR group, conducted in the last years, allowed to the identification of an intricate network between the three different classes of noncoding factors in several cancer types (Figure). Moreover, several studies focused on circulating ncRNAs in cancer patients, underling their promising use as novel powerful biomarkers. The obtained results lead to a deeper understanding of the molecular pathways involved in tumorigenesis and represent the basis for the identification of novel powerful biomarkers.

In the last year the research activiyt of the group led to the possibility of patenting new biomarkers such as miRNA and circRNA.

In particular 3 projects led to the filing of 3 patents:

1. The identification of a 4 miRNAs signature associated with the occurence of relapse in patients with head and neck cancers.
2. The identification of a circRNA as a biomarker involved in the recurrence of breast tumors, in particular TNBC.
3. The identification of a miRNA signature as biomarkers for the development of mucositis. A project in collaboration with the San Gallicano Institute.