Evidence map›Paper›PMID 28671671›Full record

ArticleOncogene2017

Wnt/β-catenin activation and macrophage induction during liver cancer development following steatosis.

A Debebe, V Medina, C-Y Chen, I M Mahajan, C Jia, D Fu, L He, N Zeng, B W Stiles, C-L Chen and 15 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. 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
3.0field-weighted citation impact, top 8% 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, 88 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Review
  4. Article
  5. Article
  6. Article
  7. Review
  8. Article
  9. Article
  10. Article
  11. Review
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  14. Review
  15. Review
  16. Review
  17. Liver Macrophage Diversity in Health and Disease.Results and problems in cell differentiation · 2024
    Review
  18. Review
  19. Article
  20. Article

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

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors at 6 institutions in 1 country.

A DebebePharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
V MedinaPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
C-Y ChenPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
I M MahajanPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
C JiaPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
D FuCentral Laboratory for Medical Research, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, China.
L HePharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
N ZengPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
B W StilesJet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA.
C-L ChenMolecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
M WangPharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.
K-R AggarwalPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Z PengPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
J HuangPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
J ChenPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
M LiPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
T DongPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
S AtkinsPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Z BorokWill Rogers Institute Pulmonary Research Center, Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
W YuanMolecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
K MachidaMolecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
C JuPharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.
M KahnPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
D JohnsonDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
B L StilesPharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
University of Southern California · USBaylor College of Medicine · USJet Propulsion Laboratory · USRogers (United States) · USUniversity of Colorado Anschutz Medical Campus · USUniversity of Montana · 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
University of Michigan Postbaccalaureate Research Education Program (UM PREP)R25GM086262 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ALLEN, BENJAMIN · 2009 to 2024
$6.1M
Novel targets that are deregulated by loss of PTENR01CA108614 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI JOHNSON, DEBORAH L. · 2006 to 2016
$2.7M
Mechanisms of beta-catenin signaling in alveolar epithelial cell differentiationR01HL112638 · NHLBI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI BOROK, ZEA, KAHN, MICHAEL · 2013 to 2016
$2.2M
Herpes simplex virus-1 evasion of CD1d antigen presentation pathwayR01AI091987 · NIAID · UNIVERSITY OF SOUTHERN CALIFORNIA · PI YUAN, WEIMING · 2012 to 2016
$2.0M
NANOG-positive cancer stem cells in liver oncogenesis induced by alcohol and HCVR01AA025204 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI MACHIDA, KEIGO · 2017 to 2021
$1.9M
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
The role of PTEN and AKT2 in the malignant transformation of liver progenitor celR01CA154986 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI STILES, BANGYAN · 2013 to 2017
$1.7M
The mechanism of beta-cell regenerationR01DK084241 · NIDDK · UNIVERSITY OF SOUTHERN CALIFORNIA · PI STILES, BANGYAN · 2010 to 2014
$1.4M
NCI NIH HHS P30 CA014089NCI NIH HHS R01 CA108614NCI NIH HHS R01 CA154986NHLBI NIH HHS R01 HL112638NIAAA NIH HHS P50 AA011999NIAAA NIH HHS R01 AA018857NIAAA NIH HHS R01 AA025204NIAID NIH HHS R01 AI091987NIDDK NIH HHS P30 DK048522NIDDK NIH HHS R01 DK084241NIGMS NIH HHS R25 GM086262
6 · The paper itself

Abstract

Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/β-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/β-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/β-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.

Indexed as

Animalsbeta CateninCarcinogenesisCell Line, TumorFatty LiverHumansLiverLiver NeoplasmsMacrophagesNeoplastic Stem CellsObesityPhosphorylationProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseWnt Signaling Pathwaybeta CateninProto-Oncogene Proteins c-aktPTEN Phosphohydrolase

Identifiers

PMID28671671
PMCPMC5666317
OpenAlexW2734161211

What OpenQuestion holds

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LicenceCC BY-NC-ND
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.