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Int J Mol Sci. 2018 Mar 14;19(3). pii: E851. doi: 10.3390/ijms19030851.

A Comprehensive Analysis of Argonaute-CLIP Data Identifies Novel, Conserved and Species-Specific Targets of miR-21 in Human Liver and Hepatocellular Carcinoma.

Author information

1
Department of Pathology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. aaron.koenig@osumc.edu.
2
Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA. aaron.koenig@osumc.edu.
3
Department of Pathology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. barajas.10@osu.edu.
4
Department of Pathology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. guerrero.41@buckeyemail.osu.edu.
5
Department of Pathology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. kalpana.ghoshal@osumc.edu.

Abstract

MicroRNAs are ~22 nucleotide RNAs that regulate gene expression at the post-transcriptional level by binding messenger RNA transcripts. miR-21 is described as an oncomiR whose steady-state levels are commonly increased in many malignancies, including hepatocellular carcinoma (HCC). Methods known as cross-linking and immunoprecipitation of RNA followed by sequencing (CLIP-seq) have enabled transcriptome-wide identification of miRNA interactomes. In our study, we use a publicly available Argonaute-CLIP dataset (GSE97061), which contains nine HCC cases with matched benign livers, to characterize the miR-21 interactome in HCC. Argonaute-CLIP identified 580 miR-21 bound target sites on coding transcripts, of which 332 were located in the coding sequences, 214 in the 3'-untranslated region, and 34 in the 5'-untranslated region, introns, or downstream sequences. We compared the expression of miR-21 targets in 377 patients with liver cancer from the data generated by The Cancer Genome Atlas (TCGA) and found that mRNA levels of 402 miR-21 targets are altered in HCC. Expression of three novel predicted miR-21 targets (CAMSAP1, DDX1 and MARCKSL1) correlated with HCC patient survival. Analysis of RNA-seq data from SK-Hep1 cells treated with a miR-21 antisense oligonucleotide (GSE65892) identified RMND5A, an E3 ubiquitin ligase, as a strong miR-21 candidate target. Collectively, our analysis identified novel miR-21 targets that are likely to play a causal role in hepatocarcinogenesis.

KEYWORDS:

HCC; liver cancer; miR-21; miRNA

PMID:
29538313
PMCID:
PMC5877712
DOI:
10.3390/ijms19030851
[Indexed for MEDLINE]
Free PMC Article

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