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Gastroenterology. 2018 Aug 27. pii: S0016-5085(18)34918-7. doi: 10.1053/j.gastro.2018.08.032. [Epub ahead of print]

microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-associated Protein 1 to Suppress Hepatocarcinogenesis.

Author information

1
Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, Aachen Germany; Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany.
2
Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, Netherlands.
3
Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen, Germany.
4
Inserm UMR-1162, Functional Genomics of Solid Tumors, University Paris Descartes, University University Paris Diderot, University Paris 13, Labex Immuno-Oncology, Paris, France.
5
Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, Aachen Germany.
6
Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany.
7
Department of Cardiology, University Hospital Kiel, Kiel, Germany.
8
Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
9
Technische Universität München, München, Germany.
10
Department of Cell and Tissue Biology, University of California, San Francisco, California.
11
Inserm Unit U1193, University Paris-Sud, Paul Brousse Hospital, Villejuif, France.
12
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany; Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen, Germany; Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
14
Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, Aachen Germany; Department of Medicine III, University Hospital RWTH Aachen, Aachen Germany. Electronic address: tluedde@ukaachen.de.

Abstract

BACKGROUND & AIMS:

We performed an integrated analysis to identify microRNAs (miRNAs) and messenger RNAs (mRNAs) with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues.

METHODS:

We analyzed miRNA and mRNA expression profiles of liver tissues from mice with diethylnitrosamine-induced hepatocarcinogenesis, conditional expression of lymphotoxin alpha and lymphotoxin beta, or inducible expression of a Myc transgene (Tet-O-Myc mice), as well as male C57BL/6 mice (controls). miRNA mimics were expressed and miRNAs and mRNAs were knocked down in human (Huh7, Hep3B, JHH2) hepatoma cell lines; cells were analyzed for viability, proliferation, apoptosis, migration, and invasion. Cells were grown as xenograft tumors in nude mice and analyzed. We combined in silico target gene prediction with mRNA profiles from all 3 mouse models. We quantified miRNA levels in 146 fresh-frozen tissues from patients (125 HCCs, 17 matched nontumor tissues, and 4 liver samples from patients without cancer) and published human data sets and tested correlations with patient survival times using Kaplan-Meier curves and the log-rank test. Levels of NUSAP1 mRNA were quantified in 237 HCCs and 5 nontumor liver samples using the TaqMan assay.

RESULTS:

Levels of the miRNA 193a-5p (MIR193A-5p) were reduced in liver tumors from all 3 mouse tumor models and in human HCC samples, compared with nontumor liver tissues. Expression of a MIR193A-5p mimic in hepatoma cells reduced proliferation, survival, migration, and invasion and their growth as xenograft tumors in nude mice. We found nucleolar and spindle-associated protein 1 (NUSAP1) to be a target of MIR193A-5p; HCC cells and tissues with low levels of MIR193A-5p had increased expression of NUSAP1. Increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Knockdown of NUSAP1 in Huh7 cells reduced proliferation, survival, migration, and growth as xenograft tumors in nude mice. Hydrodynamic tail-vein injections of a small hairpin RNA against NUSAP1 reduced growth of AKT1-MYC-induced tumors in mice.

CONCLUSIONS:

MIR193A-5p appears to prevent liver tumorigenesis by reducing levels of NUSAP1. Levels of MIR193A-5p are reduced in mouse and human HCC cells and tissues, leading to increased levels of NUSAP1, associated with shorter survival times of patients. Integrated analyses of miRNAs and mRNAs in tumors from mouse models can lead to identification of therapeutic targets in humans. The currently reported miRNA and mRNA profiling data have been submitted to the Gene Expression Omnibus (super-series accession number GSE102418).

KEYWORDS:

Gene Regulation; Liver Cancer; Systems Biology; Translation

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