The Study of miRNAs and Other ncRNAs in Cancer Initiation, Progression and Metastasis
The rationale of Dr. George Calin's work is straightforward: Cancer is a complex genetic disease involving structural and expression abnormalities of both coding and non-coding genes. In 2007, predictions estimated that approximately 600,000 people in the U.S. would die from cancer – that’s about one person per minute for the entire year. For almost three decades, alterations of protein-coding oncogenes and tumor suppressor genes have been considered the cause of tumorigenesis. Therefore, all attempts to develop and test new cancer gene therapy strategies and to develop new diagnostic and prognostic markers involved protein-coding genes. With the discovery, in the last few years, of thousands of genes that produce small, non-coding RNA (ncRNA) transcripts with no significant open reading frame named microRNAs (miRNAs), it has become evident that the genomic complexity of the cancer cell is far greater than expected. The development and testing of non-codingRNAs cancer markers and of miRNA-based cancer gene therapy are rational further steps in the identification of new options for curing cancer patients.
Non-coding RNAs (ncRNAs) are strangers in the genomic galaxy and represent genes that do not translate into proteins and can range in size from 19 nucleotides to 25 nucleotides (nt) – for the large family of miRNAs that modulate development in several organisms, including mammals – to more than 10,000 nt for RNAs involved in gene silencing in higher eukaryotes. miRNAs typically are excised from a 60-nt to 110-nt hairpin precursor (fold-back) RNA structure (pre-miRNA) that is transcribed from a larger primary transcript (pri-miRNA). Functionally, miRNAs reduce the levels of many of their target transcripts, as well as the amount of protein encoded by these transcripts, by direct and imperfect interaction with messenger RNA (miRNA::mRNA). The list of proposed miRNA functions includes hematopoietic B-cell lineage fate (miR-181), B-cell survival (miR-15a and miR-16-1), cell proliferation control (miR-125b and let-7), brain patterning (miR-430), pancreatic cell insulin secretion (miR-375) and adipocyte development (miR-145). My laboratory also focused on the identification of new long ncRNAs such as ultraconserved genes (UCGs), which are a new class of non-coding RNAs that are direct miRNA targets and also altered in human cancers. Ultraconserved sequences (UCRs) are, by definition, pieces of human genome located within both intra- and intergenic regions that absolutely are conserved – 100% identity with no insertions or deletions – between orthologous regions of human, rat and mouse genomes. We showed that UCRs are frequently located at fragile sites and genomic regions involved in cancers, and that profiling genome-wide UCRs reveals distinct signatures in human cancers. These findings argue that non-coding genes are involved in tumorigenesis to a greater extent than previously thought and offer the perspective of identification of signatures associated with diagnosis, prognosis and response to treatment composed by various categories of non-coding RNA genes.
During the last few years, we pioneered the idea that small non-coding RNAs – microRNA genes (miRNAs) – are involved in human tumorigenesis (Calin et al., Proc Natl Acad Sci USA, 2002). We also proved that another family of ncRNAs named ultraconserved genes (UCGs) are involved in human cancers and directly interact with miRNAs (Calin et al., Cancer Cell, 2007). Finally, we focused on how to quickly translate these discoveries to better diagnosis and treat cancer patients (Fabbri et al., JAMA, 2011).