Proteo-Genomics Approaches to Assess Molecular Circuits of Epithelial Cancer Invasion : Implication of MicroRNA's - MECI
Coordinating Institution:
Université du Luxembourg
Contracting Partner(s):
CRP Gabriel Lippmann ,
CRP-Santé
Other Partner(s):
Institut de Génétique et de Biologie Moléculaire, Strasbourg (F) ,
Institut de Génétique Moléculaire de Montpellier (F)
From: 01/01/2008
To: 31/12/2009
Budget: 372,490.00€
Contact(s):
Friederich Evelyne
Summary
Epithelial to mesenchymal transition (EMT) is a fundamental, transient biological process implicated in gastrulation or neural crest cell migration during embryogenesis as well as in tissue regeneration and inflammation-associated wound healing in adults. In addition, the complex EMT program is reactivated in carcinoma cells allowing them to dissociate from the primary tumour to invade the surrounding tissues and to disseminate to distant organ sites. The principal hallmarks of EMT are the loss of epithelial cells intercellular junctions, down-regulation of epithelial markers and a profound reorganisation of the actin cytoskeleton linked to morphological and functional changes.
Conversely, up-regulation of mesenchymal markers and the acquisition of a fibroblast-like motile and invasive phenotype are observed. In addition to the profound alterations of the expression profiles of messengers RNA (mRNAs) encoding genes observed during EMT, recent findings show that microRNAs (miRNAs) which are ~22nt-long non-coding RNAs that coordinate gene expression at the post-transcriptional level, also contribute to this process. To identify miRNAs that are early expressed during EMT and may regulate this process, we used a human breast cancer cell line conditionally expressing the transcription factor SNAI1 which is an EMT-inducer.
We analysed high-throughput time-resolved transcriptomic data using a novel meta-regulation network approach that we established to identify central EMT-associated miRNAs. This method highlighted the up-regulated miR-661, a miRNA with so far no reported role in EMT. MiR-661 was required for efficient invasion of breast cancer cells via the destabilization of two of its predicted mRNA targets, the cell-cell adhesion protein Nectin-1 and the lipid transferase StarD10. Importantly, analysis of public transcriptomic data from a cohort of 295 well-characterized breast tumor specimen revealed that expression of StarD10 is highly associated with markers of luminal subtypes while its loss negatively correlated with the poor prognosis and EMT-related, basal-like subtype.
Collectively, our meta-regulation network analysis approach revealed a non-predicted link between SNAI1-triggered EMT and the down-regulation of Nectin-1 and StarD10 via the up-regulation of miR-661 which may contribute to the invasion of breast cancer cells and poor disease outcome. In the future, a novel set of miRNAs candidates predicted by our method to be central to EMT will be functionally tested. Finally, our transcriptomic analysis approach will be completed by the inclusion of proteomics data.
Refereed Scientific Publications:
- Saumet, A., G. Vetter, M. Bouttier, E. Portales-Casamar, W.W. Wasserman, T. Maurin, B. Mari, P. Barbry, L. Vallar, E. Friederich, K. Arar, B. Cassinat, C. Chomienne, and C.H. Lecellier. 2009. Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. Blood. 113:412-21.
- Vetter, G., A. Le Bechec, J. Muller, A. Muller, M. Moes, M. Yatskou, Z. Al Tanoury, O. Poch, L. Vallar, and E. Friederich. 2009. Time-resolved analysis of transcriptional events during SNAI1-triggered epithelial to mesenchymal transition. Biochem Biophys Res Commun. 385:485-91.
Figure: Identification of miRNA targets by combining miRNA- and mRNA microarray data analyses with an in silico approach