MicroRNA 10b promotes abnormal expression of the protooncogene c-Jun in metastatic breast cancer cells

Revital Knirsh, Iris Ben-Dror, Shira Modai, Noam Shomron, Lily Vardimon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)59932-59944
Number of pages13
JournalOncotarget
Volume7
Issue number37
DOIs
StatePublished - 2016

Funding

FundersFunder number
Israel Cancer Association

    Keywords

    • Metastatic breast cancer
    • NF1
    • RhoC
    • c-Jun
    • miR10-b

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