NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte

  1. SM Nashir Udden
  2. Youn-Tae Kwak
  3. Victoria Godfrey
  4. Md Abdul Wadud Khan
  5. Shahanshah Khan
  6. Nicolas Loof
  7. Lan Peng
  8. Hao Zhu
  9. Md. Hasan Zaki  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. MD Anderson Cancer Center, United States

Abstract

Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.

Data availability

All data generated or analyzed during this study are included in the manuscript and supplemental materials. 16S rRNA gene sequencing of gut bacteria was analyzed and the raw data were submitted to NCBI. Data source and accession numbers were included in the manuscript.

The following data sets were generated

Article and author information

Author details

  1. SM Nashir Udden

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Youn-Tae Kwak

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Victoria Godfrey

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Md Abdul Wadud Khan

    Department of Surgical Oncology, MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shahanshah Khan

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicolas Loof

    Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lan Peng

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Hao Zhu

    Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8417-9698
  9. Md. Hasan Zaki

    Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    hasan.zaki@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9002-5399

Funding

Cancer Prevention and Research Institute of Texas (RP160169)

  • Md. Hasan Zaki

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed under the protocol #2016-101683 which was approved by the Institutional Animal Care and Use Committee (IACUC). All animal experiments were conducted in accordance with the IACUC guidelines and the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Reviewing Editor

  1. Xuetao Cao, Zhejiang University School of Medicine, China

Publication history

  1. Received: July 24, 2018
  2. Accepted: March 25, 2019
  3. Accepted Manuscript published: April 16, 2019 (version 1)
  4. Version of Record published: April 25, 2019 (version 2)

Copyright

© 2019, Udden et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. SM Nashir Udden
  2. Youn-Tae Kwak
  3. Victoria Godfrey
  4. Md Abdul Wadud Khan
  5. Shahanshah Khan
  6. Nicolas Loof
  7. Lan Peng
  8. Hao Zhu
  9. Md. Hasan Zaki
(2019)
NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte
eLife 8:e40396.
https://doi.org/10.7554/eLife.40396

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