NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30990169.
- Also identified by DOI 10.7554/eLife.40396 and PMC identifier 6483596.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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). <i>Nlrp12<sup>-/-</sup></i> mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, <i>Nlrp12<sup>-/-</sup></i> tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in <i>Nlrp12<sup>-/-</sup></i> mouse livers. Signaling analyses demonstrated higher JNK activation in <i>Nlrp12<sup>-/-</sup></i> HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of <i>Nlrp12<sup>-/-</sup></i> hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.
Medical subject headings
- Carcinoma, Hepatocellular
- Down-Regulation
- Hepatocytes
- Intracellular Signaling Peptides and Proteins
- JNK Mitogen-Activated Protein Kinases
- Liver Neoplasms