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PMID: 18328430 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.

Cancer cell ·Vol. 13 ·No. 3 ·2008-03-00 ·Pages 272-86

Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A

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.

MeSH Terms

Adenocarcinoma/genetics,metabolism,pathology Apoptosis/genetics Apoptosis Regulatory Proteins/genetics,metabolism Bcl-2-Like Protein 11 Cell Cycle/genetics Cell Cycle Proteins/genetics,metabolism Cell Line, Tumor Cell Proliferation Cyclin-Dependent Kinase Inhibitor p21/genetics,metabolism DNA-Binding Proteins/genetics,metabolism E2F1 Transcription Factor/genetics,metabolism Feedback, Physiological Gene Expression Regulation, Neoplastic Humans Membrane Proteins/genetics,metabolism MicroRNAs/metabolism Minichromosome Maintenance Complex Component 7 Nuclear Proteins/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism RNA Processing, Post-Transcriptional RNA, Messenger/metabolism Stomach Neoplasms/genetics,metabolism,pathology Time Factors Transfection Transforming Growth Factor beta/metabolism Up-Regulation

Chemicals

Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 CDKN1A protein, human Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p21 DNA-Binding Proteins E2F1 Transcription Factor E2F1 protein, human Membrane Proteins MicroRNAs Nuclear Proteins Proto-Oncogene Proteins RNA, Messenger Transforming Growth Factor beta MCM7 protein, human Minichromosome Maintenance Complex Component 7

Authors & Affiliations

17 authors, click to expand affiliations / ORCID

Petrocca Fabio

Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA.

Visone Rosa

Onelli Mariadele Rapazzotti

Shah Manisha H

Nicoloso Milena S

de Martino Ivana

Iliopoulos Dimitrios

Pilozzi Emanuela

Liu Chang-Gong

Negrini Massimo

Cavazzini Luigi

Volinia Stefano

Alder Hansjuerg

Ruco Luigi P

Baldassarre Gustavo

Croce Carlo M

Vecchione Andrea

Article Info

Journal

Cancer cell

Abbr.

Cancer Cell

ISSN

1878-3686

DOI

10.1016/j.ccr.2008.02.013

Published

2008-03-00

Pages

272-86

Language

English

Region

United States

NLM ID

101130617

Subset

Grants

Telethon · GTF03012 · Italy

External Links

PubMed source DOI: 10.1016/j.ccr.2008.02.013 View journal details

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E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.

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