MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia

Jia Yu, David G. Ryan, Spiro Getsios, Michelle Oliveira-Fernandes, Anees Fatima, Robert M. Lavker

Research output: Contribution to journalArticlepeer-review

214 Scopus citations

Abstract

Despite their potential to regulate approximately one-third of the whole genome, relatively few microRNA (miRNA) targets have been experimentally validated, particularly in stratified squamous epithelia. Here we demonstrate not only that the lipid phosphatase SHIP2 is a target of miRNA-205 (miR-205) in epithelial cells, but, more importantly, that the corneal epithelial-specific miR-184 can interfere with the ability of miR-205 to suppress SHIP2 levels. This is the first example of a miRNA negatively regulating another to maintain levels of a target protein. Interfering with miR-205 function by using a synthetic antagomir, or by the ectopic expression of miR-184, leads to a coordinated damping of the Akt signaling pathway via SHIP2 induction. This was associated with a marked increase in keratinocyte apoptosis and cell death. Aggressive squamous cell carcinoma (SCC) cells exhibited elevated levels of miR-205. This was associated with a concomitant reduction in SHIP2 levels. Partial knockdown of endogenous miR-205 in SCCs markedly decreased phosphorylated Akt and phosphorylated BAD levels and increased apoptosis. We were able to increase SHIP2 levels in SCC cells after inhibition of miR-205. Therefore, miR-205 might have diagnostic value in determining the aggressivity of SCCs. Blockage of miR-205 activity with an antagomir or via ectopic expression of miR-184 could be novel therapeutic approaches for treating aggressive SCCs.

Original languageEnglish (US)
Pages (from-to)19300-19305
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number49
DOIs
StatePublished - Dec 9 2008

ASJC Scopus subject areas

  • General

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