H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b.
H19 is a long non-coding RNA precursor of miR-675 microRNA. 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.
INSERM U908, Cell Plasticity and Cancer, F-59655, Villeneuve d'Ascq, France.|University of Lille, F-59655, Villeneuve d'Ascq, France.
Constance
C
Vennin
CNRS UMR 8161, F-59021, Lille, France.
Nathalie
N
Spruyt
CNRS UMR 8161, F-59021, Lille, France.
Fatima
F
Dahmani
INSERM U908, Cell Plasticity and Cancer, F-59655, Villeneuve d'Ascq, France.|University of Lille, F-59655, Villeneuve d'Ascq, France.
Sylvain
S
Julien
Paoli-Calmettes Institute, Aix -Marseille University, F-13009, Marseille, France.
François
F
Bertucci
Paoli-Calmettes Institute, Aix -Marseille University, F-13009, Marseille, France.
Pascal
P
Finetti
PLETHA, Institut Pasteur Lille, F-59019, Lille, France.
Thierry
T
Chassat
CNRS UMR 8161, F-59021, Lille, France.
Roland P
RP
Bourette
INSERM U908, Cell Plasticity and Cancer, F-59655, Villeneuve d'Ascq, France.|University of Lille, F-59655, Villeneuve d'Ascq, France.
Xuefen
X
Le Bourhis
INSERM U908, Cell Plasticity and Cancer, F-59655, Villeneuve d'Ascq, France.|University of Lille, F-59655, Villeneuve d'Ascq, France.
Eric
E
Adriaenssens
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010641:Phenotype; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C094335:H19 long non-coding RNA; C548379:MIRN675 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C067419:CBL protein, human
CBL; H19; breast cancer; miRNA; tyrosine kinase receptor