title: E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.
abstract: Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA-directed negative feedback loop. Furthermore, upregulation of these miRNAs impairs the TGFbeta tumor suppressor pathway, interfering with the expression of CDKN1A (p21(Waf1/Cip1)) and BCL2L11 (Bim). Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Petrocca
authors.forename: Rosa
authors.initials: R
authors.lastname: Visone
authors.forename: Mariadele Rapazzotti
authors.initials: MR
authors.lastname: Onelli
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.forename: Milena S
authors.initials: MS
authors.lastname: Nicoloso
authors.forename: Ivana
authors.initials: I
authors.lastname: de Martino
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pilozzi
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Luigi
authors.initials: L
authors.lastname: Cavazzini
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Luigi P
authors.initials: LP
authors.lastname: Ruco
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7