MicroRNAs impair MET-mediated invasive growth

MicroRNAs (miRNAs) are a recently identified class of non-coding, 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 (HGF), 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. Moreover, exogenous expression of miR-34B, miR-34C and miR-199a* in cancer cells blocked MET-induced signal transduction and the execution of the invasive growth program in response to HGF. In addition, we provide evidence that expression of these miRNAs hampered the execution of the invasive growth program also in cancer cells overexpressing a constitutively active MET. 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.