The NOD-like receptor NLRP12 plays a critical role in hepatic inflammation and cancer
| Autor: | Hasan Zaki, SM Nashir Udden |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 202:194.44-194.44 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.202.supp.194.44 |
| Popis: | Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic NOD-like receptor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Cancer genomics database analysis showed that NLRP12 expression is significantly reduced in human HCC and around 2% HCC patients carry mutations in NLRP12. 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 pathway analyses demonstrated higher JNK activation in Nlrp12−/− HCC and cultured hepatocytes during stimulation with microbial pattern molecules. Inhibition of JNK activation or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12−/− hepatocytes. In summary, this study demonstrated for the first time that NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes. |
| Databáze: | OpenAIRE |
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