Journal
CARCINOGENESIS
Volume 39, Issue 3, Pages 447-457Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgx146
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Funding
- (Junta de Andalucia) [BIO-0139, CTS-1406, PI-639-2012, PI-0541-2013]
- (MINECO) [BFU2013-43282-R, BFU2016-80360-R]
- Miguel Servet Program [Proyectos de Investigacion en Salud FIS - Instituto de Salud Carlos III]
- European Union (ERDF/ESF, Investing in your future)
- CIBERobn [PI16/00134]
- Instituto de Salud Carlos III
- (CIBERONC) [CB16/12/00295]
- MD Anderson Foundation Biobank [B.0000745]
- [PI16/00264]
- [CP15/00156]
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Ghrelin gene generates several variants that regulate multiple pathophysiological functions, including tumor-related processes. In1-ghrelin is a splicing variant that was previously shown to be overexpressed in breast cancer (BCa), where it correlated with proliferation markers; however, its possible association with clinical outcome of BCa patients and underlying mechanisms are still unknown. To address this issue, expression levels and clinical associations of In1-ghrelin were analyzed in a cohort of 117 BCa samples. Additionally, a battery of cellular and molecular assays was implemented using two BCa cell lines (MCF-7 and MDA-MB-231), wherein the role of In1-ghrelin on proliferation, migration, dedifferentiation and signaling pathways was explored. The results generated revealed that high expression of In1-ghrelin in BCa samples was associated with lymph node metastasis and reduced disease-free survival. Indeed, In1-ghrelin overexpression stimulated proliferation and migration in MCF-7 and MDA-MB-231 cells. Similar results were found by treating MDA-MB-231 and MCF-7 with In1-ghrelin-derived peptides. Conversely, In1-ghrelin silencing decreased proliferation and migration capacities of MDA-MB-231. Furthermore, In1-ghrelin (but not ghrelin) overexpression increased the capacity to form mammospheres in both cell lines. These effects could be associated with activation of MAPK-ERK, Jag1/Notch, Wnt/beta-catenin and/or TGF-beta 1 pathways. Altogether, our data indicate that In1-ghrelin could play relevant functional roles in the regulation of BCa development and progression and may provide insights to identify novel biomarkers and new therapeutic approaches for this pathology.
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