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Cited by 13Drug Transport and Resistance MechanismsLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage

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Collino, Agnese, Termanini, Alberto, Nicoli, Paola, Diaferia, Giuseppe, Polletti, Sara, Recordati, Camilla, Castiglioni, Vittoria, Caruso, Donatella +3 more·2018·PLOS Genetics
DOI 10.1371/journal.pgen.1007380PMC PMC5957449
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Abstract

Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.

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  • Many GST protein family members act as tumor promoters by influencing reactive oxygen species (ROS).

    “Many GST protein family members act as tumor promoters by influencing reactive oxygen species (ROS) (51–56).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [51]

    The Results sections on hepatocyte gene expression and detoxification enzymes report that several glutathione S-transferases are upregulated in Mdr2-/- livers and place them within detoxification pathways active during tumor development. They also report an oxidative-stress response, but do not show that GST family members themselves act as tumor promoters by influencing ROS. No page number is available in our copy. (LLM, conf=0.83)

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Authors
Collino, A., Termanini, A., Nicoli, P., Diaferia, G., Polletti, S., Recordati, C., Castiglioni, V., Caruso, D., Mitro, N., Natoli, G., & Ghisletti, S.
Affiliations
  • European Institute of Oncology (IT)
  • Humanitas University (IT)
  • Fondazione Filarete (IT)
  • University of Milan (IT)
Corresponding author
  • Mitro, Nico
  • Natoli, Gioacchino
  • Ghisletti, Serena
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2018-05-07
Volume
14
Issue
5
Pages
e1007380
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1007380
PMC
PMC5957449
OpenAlex
W2800124833
Cited by
13
References
3
Citations by year
2025: 3 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 2
FWCI
0.47
Type
journal article
Language
en
Update notices
new_version (2018-05-17)
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Italian Ministry of Health (GR)
  • European Community's Seventh Framework Programme (MODHEP consortium)
  • Italian Association for Research on Cancer (MFAG)
  • Italian Ministry of Education, University and Research (INCA)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
hepatocarcinogenesis, bile acids, Mdr2 knockout mice, constitutive androstane receptor, metabolic detoxification, chronic inflammation, tumor regression
MeSH terms
Constitutive Androstane Receptor, ATP-Binding Cassette Sub-Family B Member 4, Androstanols, Animals, Bile Acids and Salts, Cell Transformation, Neoplastic, Hepatitis, Liver, Liver Neoplasms, Inactivation, Metabolic, Signal Transduction, Transcriptional Activation, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Gene Expression Profiling, Gene Ontology

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