H19non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b

// Constance Vennin 1,2 , Nathalie Spruyt 3 , Fatima Dahmani 3 , Sylvain Julien 1,2 , François Bertucci 4 , Pascal Finetti 4 , Thierry Chassat 5 , Roland P. Bourette 3 , Xuefen Le Bourhis 1,2 and Eric Adriaenssens 1,2 1 INSERM U908, Cell Plasticity and Cancer, F-59655, Villeneuve d’Ascq, France 2 University of Lille, F-59655, Villeneuve d’Ascq, France 3 CNRS UMR 8161, F-59021, Lille, France 4 Paoli-Calmettes Institute, Aix -Marseille University, F-13009, Marseille, France 5 PLETHA, Institut Pasteur Lille, F-59019, Lille, France Correspondence to: Eric Adriaenssens, email: // Keywords : H19, miRNA, breast cancer, CBL, tyrosine kinase receptor Received : April 28, 2015 Accepted : July 16, 2015 Published : July 22, 2015 Abstract H19 is a long non-coding RNA precursor of miR-675microRNA. H19 is increasingly described to play key roles in the progression and metastasis of cancers from different tissue origins. We have previously shown that the H19 gene is activated by growth factors and increases breast cancer cell invasion. In this study, we established H19 /miR-675 ectopic expression models of MDA-MB-231 breast cancer cells to further investigate the underlying mechanisms of H19 oncogenic action. We showed that overexpression of H19 /miR-675 enhanced the aggressive phenotype of breast cancer cells including increased cell proliferation and migration in vitro , and increased tumor growth and metastasis in vivo . Moreover, we identified ubiquitin ligase E3 family (c-Cbl and Cbl-b) as direct targets of miR-675 in breast cancer cells. Using a luciferase assay, we demonstrated that H19 , through its microRNA, decreased both c-Cbl and Cbl-b expression in all breast cancer cell lines tested. Thus, by directly binding c-Cbl and Cbl-b mRNA, miR-675 increased the stability and the activation of EGFR and c-Met, leading to sustained activation of Akt and Erk as well as enhanced cell proliferation and migration. Our data describe a novel mechanism of protumoral action of H19 in breast cancer.