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Cited by 143Immune Response and InflammationCancer-related Molecular PathwaysImmunotherapy and Immune Responses

The Human TLR Innate Immune Gene Family Is Differentially Influenced by DNA Stress and p53 Status in Cancer Cells

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Shatz, Maria, Menendez, Daniel, Resnick, Michael A.·2012·Cancer Research
DOI 10.1158/0008-5472.can-11-4134PMC PMC3443562

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Abstract

The transcription factor p53 regulates genes associated with a wide range of functions, including the Toll-like receptor (TLR) set of innate immunity genes, suggesting that p53 also modulates the human immune response. The TLR family comprises membrane glycoproteins that recognize pathogen-associated molecular patterns (PAMP) and mediate innate immune responses, and TLR agonists are being used as adjuvants in cancer treatments. Here, we show that doxorubicin, 5-fluorouracil, and UV and ionizing radiation elicit changes in TLR expression that are cell line- and damage-specific. Specifically, treatment-induced expression changes led to increased downstream cytokine expression in response to ligand stimulation. The effect of DNA stressors on TLR expression was mainly mediated by p53, and several p53 cancer-associated mutants dramatically altered the pattern of TLR gene expression. In all cell lines tested, TLR3 induction was p53-dependent, whereas induction of TLR9, the most stress-responsive family member, was less dependent on status of p53. In addition, each of the 10 members of the innate immune TLR gene family tested was differentially inducible. Our findings therefore show that the matrix of p53 status, chromosome stress, and responsiveness of individual TLRs should be considered in TLR-based cancer therapies. Cancer Res; 72(16); 3948–57. ©2012 AACR.

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  • TLR4 was only expressed in SaOS2 cells.

    “Consistent with our previous findings, TLR8 mRNA was not detected in either cell type while TLR4 was only expressed in SaOS2 cells [25].”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [25]

    The Results section on p53 modulation of TLR genes says that all TLRs except TLR8 are expressed in U2OS cells, which includes TLR4. It also reports increased TLR4 mRNA in SaOS2 cells, so expression was not limited to SaOS2. (LLM, conf=0.91)

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  • TLR8 mRNA was not detected in either HCT116 or SaOS2 cells.

    “Consistent with our previous findings, TLR8 mRNA was not detected in either cell type while TLR4 was only expressed in SaOS2 cells [25].”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [25]

    The Results section on p53 modulation explicitly says that TLR8 mRNA was not detected in SaOS2 cells. The Results section on expression across cancer cell lines mentions HCT116, but does not say whether TLR8 mRNA was detected there; that part of the claim is unsupported by the passages in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses.

    “We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses.”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [25]

  • p53 can directly influence expression of the TLR gene family and downstream immune/inflammatory responses.

    “Since p53 can directly influence expression of the TLR gene family and downstream immune/inflammatory responses [24–26]”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [25]

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Cites

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Authors
Shatz, M., Menendez, D., & Resnick, M. A.
Affiliations
  • National Institutes of Health (US)
  • Authors' Affiliation: Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, North Carolina
Corresponding author
Resnick, Michael A.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2012-08-14
Volume
72
Issue
16
Pages
3948-3957
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-11-4134
PMC
PMC3443562
OpenAlex
W2156245645
Cited by
143
References
8
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 9 · 2021: 19 · 2020: 13 · 2019: 10 · 2018: 11 · 2017: 17 · 2016: 11 · 2015: 14 · 2014: 12 · 2013: 6
FWCI
4.48
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Environmental Health Sciences (ZIAES065079, Z01ES065079)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
Toll-like receptors, p53, DNA damage response, innate immunity, TLR3, TLR9, mutant p53, doxorubicin, 5-fluorouracil, ultraviolet radiation, ionizing radiation, cytokine expression, cancer immunotherapy
MeSH terms
Adenocarcinoma, Bone Neoplasms, Breast Neoplasms, Cell Line, DNA Damage, DNA, Neoplasm, Doxorubicin, Female, Fluorouracil, Humans, Immunity, Innate, Mutation, Neoplasms, Promoter Regions, Genetic, Osteosarcoma, Transfection, Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cytokines, Response Elements, Toll-Like Receptors, MCF-7 Cells

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