Evidence map›Paper›PMID 26582088›Full record

ArticleGastroenterology2016

TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-Initiating Stem-Like Cells in Livers of Mice.

Dinesh Babu Uthaya Kumar, Chia-Lin Chen, Jian-Chang Liu, Douglas E Feldman, Linda S Sher, Samuel French, Joseph DiNorcia, Samuel W French, Bita V Naini, Sunhawit Junrungsee and 3 more

Erratum issuedAbstract read
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In one paragraph

Article in Gastroenterology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 63 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
63citing papers in PubMed, 1 pooled it
4.5field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

63 citing papers in PubMed, 1 synthesis or guideline pooled it, 102 citations in OpenAlex.

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3 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 2 institutions in 1 country.

Dinesh Babu Uthaya KumarDepartment of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, California.
Chia-Lin ChenDepartment of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, California.
Jian-Chang LiuDepartment of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, California.
Douglas E FeldmanDepartment of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, California.
Linda S SherDepartment of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, California.
Samuel FrenchDepartment of Pathology, Harbor-University California Los Angeles Medical Center, Los Angeles, California.
Joseph DiNorciaDepartment of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, California.
Samuel W FrenchDepartment of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California.
Bita V NainiDepartment of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.
Sunhawit JunrungseeDepartment of Surgery, University of California Los Angeles School of Medicine, Los Angeles, California.
Vatche Garen AgopianDepartment of Surgery, University of California Los Angeles School of Medicine, Los Angeles, California.
Ali ZarrinparDepartment of Surgery, University of California Los Angeles School of Medicine, Los Angeles, California.
Keigo MachidaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, California; Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, Los Angeles, California. Electronic address: keigo.machida@med.usc.edu.
University of Southern California · USUniversity of California, Los Angeles · US

Funding

USC/NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORTP30CA014089 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI MYLES G COCKBURN · 1985 to 2026
$181.4M
The Southernearch Center for ALPD and CirrhosisP50AA011999 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ANNA S. GUKOVSKAYA · 1999 to 2026
$45.8M
USC RESEARCH CENTER FOR LIVER DISEASES: PILOT PROGRAMSP30DK048522 · NIDDK · UNIVERSITY OF SOUTHERN CALIFORNIA · PI OOKHTENS, MURAD · 1995 to 2020
$21.8M
NON-PARENCHYMAL LIVER CELL CORER24AA012885 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI TSUKAMOTO, HIDEKAZU · 2001 to 2025
$8.1M
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCVR01AA018857 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI MACHIDA, KEIGO · 2009 to 2013
$1.8M
ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSISU01AA021898 · NIAAA · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · PI FRENCH, SAMUEL WILLIAM · 2013 to 2017
$1.0M
NCI NIH HHS P30 CA014089NCI NIH HHS P30CA 014089NIAAA NIH HHS P50 AA011999NIAAA NIH HHS P50AA011999NIAAA NIH HHS R01 AA018857NIAAA NIH HHS R01AA018857NIAAA NIH HHS R24 AA012885NIAAA NIH HHS R24AA012885NIAAA NIH HHS U01 AA021898NIAAA NIH HHS U01AA021898NIDDK NIH HHS P30 DK048522NIDDK NIH HHS P30DK048522
6 · The paper itself

Abstract

BACKGROUND &

aimsObesity and alcohol consumption contribute to steatohepatitis, which increases the risk for hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCCs). Mouse hepatocytes that express HCV-NS5A in liver up-regulate the expression of Toll-like receptor 4 (TLR4), and develop liver tumors containing tumor-initiating stem-like cells (TICs) that express NANOG. We investigated whether the TLR4 signals to NANOG to promote the development of TICs and tumorigenesis in mice placed on a Western diet high in cholesterol and saturated fat (HCFD).

methodsWe expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4-/- (C57Bl6/10ScN), and wild-type control mice. Mice were fed a HCFD for 12 months. TICs were identified and isolated based on being CD133+, CD49f+, and CD45-. We obtained 142 paraffin-embedded sections of different stage HCCs and adjacent nontumor areas from the same patients, and performed gene expression, immunofluorescence, and immunohistochemical analyses.

resultsA higher proportion of NS5A Tg mice developed liver tumors (39%) than mice that did not express HCV NS5A after the HCFD (6%); only 9% of Tlr4-/- NS5A Tg mice fed HCFD developed liver tumors. Livers from NS5A Tg mice fed the HCFD had increased levels of TLR4, NANOG, phosphorylated signal transducer and activator of transcription (pSTAT3), and TWIST1 proteins, and increases in Tlr4, Nanog, Stat3, and Twist1 messenger RNAs. In TICs from NS5A Tg mice, NANOG and pSTAT3 directly interact to activate expression of Twist1. Levels of TLR4, NANOG, pSTAT3, and TWIST were increased in HCC compared with nontumor tissues from patients.

conclusionsHCFD and HCV-NS5A together stimulated TLR4-NANOG and the leptin receptor (OB-R)-pSTAT3 signaling pathways, resulting in liver tumorigenesis through an exaggerated mesenchymal phenotype with prominent Twist1-expressing TICs.

Indexed as

AdultAgedAged, 80 and overAnimalsApolipoproteins ECell LineCell MovementCell Self RenewalCell Transformation, NeoplasticDiet, High-FatDisease Models, AnimalEpithelial-Mesenchymal TransitionFemaleGene Expression Regulation, NeoplasticHomeodomain ProteinsHumansApolipoproteins EHomeodomain ProteinsNanog Homeobox ProteinNanog protein, mouseNS-5 protein, hepatitis C virusNuclear ProteinsRNA-Dependent RNA PolymeraseSTAT3 protein, humanStat3 protein, mouseSTAT3 Transcription FactorTLR4 protein, humanTlr4 protein, mouseToll-Like Receptor 4TWIST1 protein, humanTwist1 protein, mouseTwist-Related Protein 1Viral Nonstructural ProteinsHCCHCVNASHObesity

Identifiers

PMID26582088
PMCPMC4766021
OpenAlexW2203341275

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.