title: Usp18 regulates epidermal growth factor (EGF) receptor expression and cancer cell survival via microRNA-7.
abstract: Epidermal growth factor receptor (EGFR) is involved in development and progression of many human cancers. We have previously demonstrated that the ubiquitin-specific peptidase Usp18 (Ubp43) is a potent regulator of EGFR protein expression. Here we report that the 3'-untranslated region (3'-UTR) of the EGFR message modulates RNA translation following cell treatment with Usp18 siRNA, suggesting microRNA as a possible mediator. Given earlier evidence of EGFR regulation by the microRNA miR-7, we assessed whether miR-7 mediates Usp18 siRNA effects. We found that Usp18 depletion elevates miR-7 levels in several cancer cell lines because of a transcriptional activation and/or mRNA stabilization of miR-7 host genes and that miR-7 acts downstream of Usp18 to regulate EGFR mRNA translation via the 3'-UTR. Also, depletion of Usp18 led to a decrease in protein levels of other known oncogenic targets of miR-7, reduced cell proliferation and soft agar colony formation, and increased apoptosis. Notably, all of these phenotypes were reversed by a specific inhibitor of miR-7. Thus, our findings support a model in which Usp18 inhibition promotes up-regulation of miR-7, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells.
authors: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors: Jason E
authors: JE
authors: Duex
authors: Laurey
authors: L
authors: Comeau
authors: Alexander
authors: A
authors: Sorkin
authors: Benjamin
authors: B
authors: Purow
authors: Benjamin
authors: B
authors: Kefas
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