HIF-inducible miR-191 promotes migration in breast cancer through complex regulation of TGF[beta]-signaling in hypoxic microenvironment

The molecular mechanisms of hypoxia induced breast cell migration remain incompletely understood. Our results show that hypoxia through hypoxia-inducible factor (HIF) brings about a time-dependent increase in the level of an oncogenic microRNA, miR-191 in various breast cancer cell lines. miR-191 en...

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Bibliographic Details
Published in:Scientific reports 2015-04, Vol.5, p.9650
Main Authors: Nagpal, Neha, Ahmad, Hafiz M, Chameettachal, Shibu, Sundar, Durai, Ghosh, Sourabh, Kulshreshtha, Ritu
Format: Article
Language:English
Subjects:
Breast cancer
Cell adhesion & migration
Cell migration
Cell proliferation
Cell survival
Connective tissue growth factor
HuR protein
Hypoxia
Hypoxia-inducible factors
Metastases
MicroRNAs
miRNA
Molecular modelling
Ribonucleic acid
RNA
RNA-binding protein
Signal transduction
Smad3 protein
Spheroids
Transforming growth factor-b
Tumor cell lines
Tumors
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Summary:The molecular mechanisms of hypoxia induced breast cell migration remain incompletely understood. Our results show that hypoxia through hypoxia-inducible factor (HIF) brings about a time-dependent increase in the level of an oncogenic microRNA, miR-191 in various breast cancer cell lines. miR-191 enhances breast cancer aggressiveness by promoting cell proliferation, migration and survival under hypoxia. We further established that miR-191 is a critical regulator of transforming growth factor beta (TGFβ)-signaling and promotes cell migration by inducing TGFβ2 expression under hypoxia through direct binding and indirectly by regulating levels of a RNA binding protein, human antigen R (HuR). The levels of several TGFβ pathway genes (like VEGFA, SMAD3, CTGF and BMP4) were found to be higher in miR-191 overexpressing cells. Lastly, anti-miR-191 treatment given to breast tumor spheroids led to drastic reduction in spheroid tumor volume. This stands as a first report of identification of a microRNA mediator that links hypoxia and the TGFβ signaling pathways, both of which are involved in regulation of breast cancer metastasis. Together, our results show a critical role of miR-191 in hypoxia-induced cancer progression and suggest that miR-191 inhibition may offer a novel therapy for hypoxic breast tumors.
ISSN:2045-2322
DOI:10.1038/srep09650