E2F1-regulated microRNAs Impair TGFbeta-dependent Cell-Cycle Arrest and Apoptosis in Gastric Cancer

Cancer Cell. 2008 Mar;13(3):272-86. doi: 10.1016/j.ccr.2008.02.013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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