title: EphrinA1 inhibits malignant mesothelioma tumor growth via let-7 microRNA-mediated repression of the RAS oncogene.
abstract: EphrinA1 binding with receptor EphA2 suppresses malignant mesothelioma (MM) growth. The mechanisms whereby EphrinA1 attenuates the MM cell (MMC) growth are not clear. In this study, we report that the activation of MMCs with EphrinA1 leads to an induction of let-7 microRNA (miRNA) expression, repression of RAS proto-oncogene and the attenuation of MM tumor growth. The expression of miRNAs was determined by reverse transcription-quantitative polymerase chain reaction and in situ hybridization. RAS expression was determined by q-PCR, western blotting and immunofluorescence. MMC proliferation and tumor growth were determined by WST-1 and Matrigel assay, respectively. EphrinA1 activation induced several fold increases in let-7a1, let-7a3, let-7f1 and let-7f2 miRNA expression in MMCs. In contrast, EphrinA1 activation significantly downregulated H-RAS, K-RAS and N-RAS expression and inhibited MMC proliferation and tumor growth. In MMCs transfected with 2'-O-methyl antisense oligonucleotides to let-7 miRNA, EphrinA1 activation failed to inhibit the proliferative response and tumor growth. In mismatch antisense oligonucleotide-treated MMCs, the proliferation and tumor growth were comparable to untreated proliferating cells. Furthermore, the transfection of MMCs with let-7a miRNA precursor inhibited RAS expression and attenuated MMC tumor growth. Our data revealed that EphrinA1 signaling induces let-7 miRNA expression and attenuates MM tumor growth by targeting RAS proto-oncogene in MMCs.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Florida, Gainesville, USA.
authors.forename: N
authors.initials: N
authors.lastname: Khodayari
authors.forename: K A
authors.initials: KA
authors.lastname: Mohammed
authors.forename: E P
authors.initials: EP
authors.lastname: Goldberg
authors.forename: N
authors.initials: N
authors.lastname: Nasreen
mesh_terms: D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D036382:Ephrin-A1 / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects*; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D036104:Receptor, EphA2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D036382:Ephrin-A1; C000715470:MAS1 protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; C542687:mirnlet7 microRNA, mouse; D036104:Receptor, EphA2