Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer

Mol Cell. 2017 Aug 3;67(3):400-410.e7. doi: 10.1016/j.molcel.2017.06.025. Epub 2017 Jul 20.

Abstract

MicroRNA-122, an abundant and conserved liver-specific miRNA, regulates hepatic metabolism and functions as a tumor suppressor, yet systematic and direct biochemical elucidation of the miR-122 target network remains incomplete. To this end, we performed Argonaute crosslinking immunoprecipitation (Argonaute [Ago]-CLIP) sequencing in miR-122 knockout and control mouse livers, as well as in matched human hepatocellular carcinoma (HCC) and benign liver tissue to identify miRNA target sites transcriptome-wide in two species. We observed a majority of miR-122 binding on 3' UTRs and coding exons followed by extensive binding to other genic and non-genic sites. Motif analysis of miR-122-dependent binding revealed a G-bulged motif in addition to canonical motifs. A large number of miR-122 targets were found to be species specific. Upregulation of several common mouse and human targets, most notably BCL9, predicted survival in HCC patients. These results broadly define the molecular consequences of miR-122 downregulation in hepatocellular carcinoma.

Keywords: Argonaute; BCL9; CLIP; HCC; Wnt; gene regulation; hepatocellular carcinoma; miR-122.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Argonaute Proteins / genetics*
  • Argonaute Proteins / metabolism
  • Binding Sites
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Case-Control Studies
  • Cell Line, Tumor
  • Cell Proliferation
  • Computational Biology
  • Databases, Genetic
  • Down-Regulation
  • Exons
  • Gene Expression Regulation, Neoplastic
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Immunoprecipitation / methods*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phenotype
  • RNA Interference
  • Species Specificity
  • Time Factors
  • Transcription Factors
  • Transcription, Genetic
  • Transcriptome*
  • Transfection
  • Wnt Signaling Pathway

Substances

  • 3' Untranslated Regions
  • Argonaute Proteins
  • BCL9 protein, human
  • BCL9 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • MIRN122 microRNA, human
  • MicroRNAs
  • Mirn122 microRNA, mouse
  • Neoplasm Proteins
  • Transcription Factors