NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte
- University of Texas Southwestern Medical Center, United States
- 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.
Article and author information
Author details
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.
Reviewing Editor
- Xuetao Cao, Zhejiang University School of Medicine, China
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.
Version history
- Received: July 24, 2018
- Accepted: March 25, 2019
- Accepted Manuscript published: April 16, 2019 (version 1)
- 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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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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