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MicroRNA 10b promotes abnormal expression of the proto-oncogene c-Jun in metastatic breast cancer cells.
- Source :
-
Oncotarget [Oncotarget] 2016 Sep 13; Vol. 7 (37), pp. 59932-59944. - Publication Year :
- 2016
-
Abstract
- MicroRNAs have been shown to act as oncogenes or tumor suppressers via various cellular pathways. Specifically, in breast cancer, upregulation of miR-10b is positively associated with aggressiveness of tumors. However, the mechanism by which miR-10b contributes to cell malignancy is largely unknown. Here we show that at the receiving end of the miR-10b pathway is the proto-oncogene c-Jun, a transcription factor that plays a critical role in stimulation of cell proliferation and tumor progression. c-Jun is known to be translationally activated by loss of cell contacts or restructuring of the cytoskeleton. A comprehensive analysis of miRNA expression exhibited a significant increase in miR-10b expression. This was supported by analysis of breast cancer cells, which showed that loss of E-cadherin in metastatic cells is accompanied by elevation of miR-10b and interestingly, by a marked increase in accumulation of c-Jun. Silencing miR-10b in metastatic breast cancer cells leads to a decline in c-Jun expression, whereas overexpression of miR-10b in HaCaT cells is sufficient to elevate the accumulation of c-Jun. The increase in c-Jun protein accumulation in metastatic cells is not accompanied by an increase in c-Jun mRNA and is not dependent on MAPK activity. Knockdown and overexpression experiments revealed that the increase is mediated by NF1 and RhoC, downstream targets of miR-10b that affect cytoskeletal dynamics through the ROCK pathway. Overall, we show the ability of miR-10b to activate the expression of c-Jun through RhoC and NF1, which represents a novel pathway for promoting migration and invasion of human cancer cells.
- Subjects :
- Breast Neoplasms pathology
Cadherins metabolism
Carcinogenesis
Cell Movement
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Neoplasm Metastasis
Proto-Oncogene Mas
Proto-Oncogene Proteins c-jun genetics
RNA, Small Interfering genetics
Up-Regulation
Breast Neoplasms metabolism
Cytoskeleton metabolism
MicroRNAs genetics
Neurofibromin 1 metabolism
Proto-Oncogene Proteins c-jun metabolism
rhoC GTP-Binding Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27494896
- Full Text :
- https://doi.org/10.18632/oncotarget.11000