Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats

Kaori Oka, Shusuke Fujioka, Yoshimi Kawamura, Yoshihiro Komohara, Takeshi Chujo, Koki Sekiguchi, Yuki Yamamura, Yuki Oiwa, Natsuko Omamiuda-Ishikawa, Shohei Komaki, Yoichi Sutoh, Satoko Sakurai, Kazuhito Tomizawa, View ORCID ProfileHidemasa Bono, Atsushi Shimizu, Kimi Araki, Takuya Yamamoto, Yasuhiro Yamada, Hiroyuki Oshiumi, View ORCID ProfileKyoko Miura
doi: https://doi.org/10.1101/2021.10.21.465383
Kaori Oka
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
bBiomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shusuke Fujioka
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
bBiomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoshimi Kawamura
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
bBiomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoshihiro Komohara
cDepartment of Cell Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takeshi Chujo
dDepartment of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Koki Sekiguchi
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuki Yamamura
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuki Oiwa
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
bBiomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Natsuko Omamiuda-Ishikawa
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shohei Komaki
eDivision of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate 028-3694, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoichi Sutoh
eDivision of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate 028-3694, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Satoko Sakurai
fDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazuhito Tomizawa
dDepartment of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
gCenter for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto 860-8556, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hidemasa Bono
hProgram of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-0046, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hidemasa Bono
Atsushi Shimizu
eDivision of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate 028-3694, Japan
iDivision of Biomedical Information Analysis, Institute for Biomedical Sciences, Iwate Medical University, Iwate 028-3694, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kimi Araki
gCenter for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto 860-8556, Japan
jInstitute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takuya Yamamoto
fDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
kInstitute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan
lMedical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan
mAMED-CREST, AMED, Tokyo 100-0004, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yasuhiro Yamada
mAMED-CREST, AMED, Tokyo 100-0004, Japan
nDivision of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroyuki Oshiumi
oDepartment of Immunology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kyoko Miura
aDepartment of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-0811, Japan
bBiomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
gCenter for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto 860-8556, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kyoko Miura
  • For correspondence: miurak@kumamoto-u.ac.jp
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted scientists to study their cancer resistance mechanisms in order to provide clues for human cancer prevention. Although cancer resistance in NMRs has been intensively investigated at the cellular level, it is still unknown how strongly resistant NMR individuals are to carcinogenesis and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration and reduced induction of inflammatory genes. NMRs harbor loss-of-function mutations in receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. A necroptosis-inducing stimulus did not increase death of NMR cells. After carcinogenic insults, leakage of the HMGB1, a marker of necrotic cell death, was not increased in NMR skin. In mice, inhibition or knockout of RIPK3 reduced immune cell infiltration and delayed the onset of chemical carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs. Further in vivo study of the unusual tissue immune system and carcinogenesis resistance of NMRs may lead to the development of new strategies to prevent carcinogenesis in humans.

Significance Statement In contrast with intensive studies of cancer resistance mechanisms in naked mole-rats (NMRs) at the cellular level, little is known about how NMR individuals respond to carcinogenesis induction, despite the fact that cell-to-cell interactions in tissues regulate carcinogenesis in vivo. Here, we demonstrate that NMRs are remarkably resistant to chemical carcinogenesis induction and characteristically have attenuated tissue inflammatory responses to carcinogenic insults. NMRs have loss-of-function mutations in RIPK3 and MLKL genes and thus cannot activate necroptosis, a type of inflammation-inducing cell death. RIPK3 inhibition in mice reduced immune cell infiltration in response to carcinogenic insults and delayed the onset of chemical-induced carcinogenesis. Our results highlight the importance of studies on dampened tissue inflammatory responses to understand cancer resistance of NMRs.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted October 23, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats
Kaori Oka, Shusuke Fujioka, Yoshimi Kawamura, Yoshihiro Komohara, Takeshi Chujo, Koki Sekiguchi, Yuki Yamamura, Yuki Oiwa, Natsuko Omamiuda-Ishikawa, Shohei Komaki, Yoichi Sutoh, Satoko Sakurai, Kazuhito Tomizawa, Hidemasa Bono, Atsushi Shimizu, Kimi Araki, Takuya Yamamoto, Yasuhiro Yamada, Hiroyuki Oshiumi, Kyoko Miura
bioRxiv 2021.10.21.465383; doi: https://doi.org/10.1101/2021.10.21.465383
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats
Kaori Oka, Shusuke Fujioka, Yoshimi Kawamura, Yoshihiro Komohara, Takeshi Chujo, Koki Sekiguchi, Yuki Yamamura, Yuki Oiwa, Natsuko Omamiuda-Ishikawa, Shohei Komaki, Yoichi Sutoh, Satoko Sakurai, Kazuhito Tomizawa, Hidemasa Bono, Atsushi Shimizu, Kimi Araki, Takuya Yamamoto, Yasuhiro Yamada, Hiroyuki Oshiumi, Kyoko Miura
bioRxiv 2021.10.21.465383; doi: https://doi.org/10.1101/2021.10.21.465383

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3691)
  • Biochemistry (7800)
  • Bioengineering (5678)
  • Bioinformatics (21295)
  • Biophysics (10582)
  • Cancer Biology (8179)
  • Cell Biology (11946)
  • Clinical Trials (138)
  • Developmental Biology (6764)
  • Ecology (10401)
  • Epidemiology (2065)
  • Evolutionary Biology (13874)
  • Genetics (9709)
  • Genomics (13074)
  • Immunology (8150)
  • Microbiology (20020)
  • Molecular Biology (7859)
  • Neuroscience (43070)
  • Paleontology (321)
  • Pathology (1279)
  • Pharmacology and Toxicology (2260)
  • Physiology (3353)
  • Plant Biology (7232)
  • Scientific Communication and Education (1313)
  • Synthetic Biology (2008)
  • Systems Biology (5539)
  • Zoology (1128)