Author Block: Smadar Avigad, Michal Hameiri-Grossman, Ian J. Cohen, Shifra Ash, Avraham Weizman, Isaac Yaniv. Schneider Children's Medical Center, Petah-Tikva, Israel, Felsenstein Medical Research Center, Petah Tikva, Israel
Ewing sarcoma (ES) is the second most frequent bone tumor in adolescents and young adults. The hallmark of the tumor is specific translocations that result in fusion genes that encode chimeric transcription factors with oncogenic properties. The most frequent translocation (85%) involves the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11.
Micro-RNAs (miRNAs) are small noncoding RNAs of 18 to 25 nucleotides that regulate protein expression. The biological functions of miRNAs are not yet fully understood. It is believed that miRNAs could direct positive or negative regulation through base pair interaction at variety of levels, depending on the specific miRNA and target base pair interaction and the cofactors that recognize them. miRNA genes were recently found to be abnormally expressed in several types of cancer.
In order to identify a possible involvement of miRNAs in ES tumorigensis, 56 ES patients and three ES cell lines were studied.
The presence of 15 miRNAs; 10 on chromosome 11 and 5 on chromosome 22 located in and around the EWS/FLI-1 breakpoints was determined at the genomic level of blood and tumor samples.
We identified loss of miRNAs in 76% of tumors and in 18% of the blood DNA samples. The deleted region spanned from one to all of the miRNAs on each chromosome in different patients. These results might imply that the miRNAs might act as tumor suppressors and be associated with ES neoplastic transformation. The fact that miRNAs are deleted in the germ line (blood DNA) might imply on a possible predisposition to ES. Following our preliminary findings, we are currently searching for the miRNAs target genes.
Interestingly, 63% of the tumors exhibited loss of at least one of the members of the let-7 miRNAs family, which is known as a negative regulator of the ras oncogene, implying its role in ES. Furthermore, in the patients who exhibited deletion of more than one of the members of the let-7 family, a high incidence of progression was identified when compared to those with only one deletion (40% vs 9%; p=0.01).
Deepening the knowledge of the involvement of miRNAs function in ES pathogenesis is an essential step towards the improvement of risk stratification and subsequently better designed treatment. The characterization of a genetic profile that could predict the development of Ewing tumors may lead to a breakthrough in ES research. Discovery of the miRNAs involved in ES has a therapeutic potential, for the development of new targeted therapies.
Additional References:
1. Diccianni MB, Calin GA, Ferracin M, Liu C-G, Negrini M, Croce
CM, and Yu A,
"MicroRNA profiles
of childhood T cell acute lymphoblastic leukemia".
2. Esquela-Kerscher A, and Slack FJ,
"Oncomirs — microRNAs
with a role in cancer".
3. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T,
Manoharan M, and Stoffel M,
"Silencing
of microRNAs in vivo with 'antagomirs'".
4. Song X, Sun Y, and Garen A,
"Roles of PSF protein
and VL30 RNA in reversible gene regulation".
5. Frenster JH, and Hovsepian JA,
"Ultrastructure
of Euchromatin Contact Points between the Closed Loops of Adjacent Interphase
Chromosomes".
6. Xu N, Tsai C-L, Lee JT,
"Transient Homologous
Chromosome Pairing Marks the Onset of X Inactivation".
A Brief History of Activator RNA.
Links to
Euchromatin Activator RNA Reviews:
Links to
Euchromatin Activator RNA Research:
Links to Ultrastructural
Probes of DNase I-Sensitive Sites:
Links to
RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma
Immuno-Pathology:
Links to Activated
T-Lymphocyte Immunotherapy:
Links to Medical
Systems Biology:
Links to Selective
Gene Transcription:
Links to RNA-Induced
Epigenetics:
Links to RNA-Induced
Embryogenesis:
Links to RNA and
Biological Causality:
Links to Reprogramming
and Neoplasia:
"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".
For Further Information and Feedback:
Phone: +1 650 367 6483
E-mail: frenster@euchromatin.net