Abstract
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.
Highlights
During recent years, many efforts have been made to untangle the pathways involved in tumor progression, to identify oncogenes and tumor suppressor genes, and to understand their interactions and mutual regulation
In the last two decades, it has been consistently proven that one of the players of the intricate scenario leading to tumorigenesis is MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF)
EKVX and HOP62 cells were obtained from NCI-60 collection; the following cell lines were obtained from American Type Culture Collection: A549 and NCI-H1299; HEK-293 (Embryonic Kidney cells); MDA-MB-435; HT-29 NCI-SNU-5, AGS, NCI-N87, and Hs746T; SK-BR-3, BT-474, and T-47D; and MCF 10A, A431, COS-7, and WI-38; RT112/84 cell line; A2780 cell line was obtained from European Collection of Cell Cultures; and MKN-7 and MKN-45 were described by Motoyama and colleagues [21]; and GTL16 was described by Giordano and colleagues [22]
Summary
Many efforts have been made to untangle the pathways involved in tumor progression, to identify oncogenes and tumor suppressor genes, and to understand their interactions and mutual regulation. MET activation as a consequence of ligand binding, receptor overexpression or interaction with other membrane receptors [2, 3], evokes pleiotropic biological responses, often defined as ‘‘invasive growth’’: this is a genetic program consisting of rate-limiting steps that takes place physiologically during embryogenesis and tissue repair, and pathologically in oncogenesis [4] This process occurs in three phases: first, cells acquire the ability to dissociate from their neighbors, breaking cell-cell junctions (scatter); they leave their original environment degrading the basal membrane and reaching the circulation (directional migration and invasion); and, they extravasate, proliferate, and eventually, undergo terminal differentiation [5]. Understanding when, how, and why this process takes place has acquired a primary importance in the perspective of developing tools capable to counteract MET aberrant activation
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