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MicroRNAs Impair MET-Mediated Invasive Growth

¹ IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo (Torino), Italy and ² Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

Requests for reprints: Silvia Giordano, Division of Molecular Oncology, Institute for Cancer Research and Treatment, S.P. 142 km 3.9, 10060, Candiolo (TO) Italy. Phone: 39-011-993-3233; Fax: 39-011-993-3225; E-mail: silvia.giordano{at}unito.it.

Key Words: MicroRNAs • MET • tyrosine kinase • invasive growth • oncogene addiction

MicroRNAs (miRNA) are a recently identified class of noncoding, endogenous, small RNAs that regulate gene expression, mainly at the translational level. These molecules play critical roles in several biological processes, such as cell proliferation and differentiation, development, and aging. It is also known that miRNAs play a role in human cancers where they can act either as oncogenes, down-regulating tumor suppressor genes, or as onco-suppressors, targeting molecules critically involved in promotion of tumor growth. One of such molecules is the tyrosine kinase receptor for hepatocyte growth factor, encoded by the MET oncogene. The MET receptor promotes a complex biological program named "invasive growth" that results from stimulation of cell motility, invasion, and protection from apoptosis. This oncogene is deregulated in many human tumors, where its most frequent alteration is overexpression. In this work, we have identified three miRNAs (miR-34b, miR-34c, and miR-199a*) that negatively regulate MET expression. Inhibition of these endogenous miRNAs, by use of antagomiRs, resulted in increased expression of MET protein, whereas their exogenous expression in cancer cells blocked MET-induced signal transduction and the execution of the invasive growth program, both in cells expressing normal levels of MET and in cancer cells overexpressing a constitutively active MET. Moreover, we show that these same miRNAs play a role in regulating the MET-induced migratory ability of melanoma-derived primary cells. In conclusion, we have identified miRNAs that behave as oncosuppressors by negatively targeting MET and might thus provide an additional option to inhibit this oncogene in tumors displaying its deregulation. [Cancer Res 2008;68(24):10128–36]