We discovered that Snail mediated the downregulation of the imprinted Dlk1-Dio3 locus, a complex genomic region containing protein-coding genes and non-coding RNAs that has been linked to tumor malignancy in lung cancer patients.
The cluster of microRNAs (miRNAs) in the DLK1-DIO3 genomic imprinted region contains several miRNAs that have a significant regulatory role in tumor proliferation and invasion.
Further, a large number of miRs observed in tumour network mapped to a specific chromosomal location in DLK1-DIO3 (Chr14q32); some of those miRs have also been associated with EMT and MET regulation.
Moreover, the high BCL-xL expression correlated with short treatment-free survival in 76 CLL patients. miR-377 is located at 14q32 in the DLK1-DIO3 region, which encodes the largest tumor suppressor miRNA cluster in humans.
The analyses revealed the involvement of both coding and non coding RNAs (SNORDs located in DLK1-DIO3 region) and support a model of stepwise progression mainly driven by epigenetic changes involving tumour vascular supply and tumoral cellular component.
These results establish the DLKI-DIO3 miRNA cluster as a critical checkpoint regulating tumor growth and metastasis and implicate epigenetic modification of the cluster in driving tumor progression.