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.