Abstract 2347: NOD-like receptor NLRP12 suppresses hepatocellular carcinoma via regulation of JNK signaling

Abstract

Abstract Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12, a member of NOD-like receptor, 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) or DEN plus hepatotoxin carbon tetrachloride (CCl4). Livers collected from wild-type and Nlrp12-/- mice at 10 and 5.5 months following DEN or DEN plus CCl4 treatment, respectively, were examined for tumor burden, histopathological changes, expression of inflammatory and tumor-promoting genes, and activation of signaling pathways. Primary hepatocytes from healthy mice were isolated, cultured, and used to assess cell signaling, apoptosis, and proliferation. Cancer genomics database analysis showed that NLRP12 expression is significantly reduced in human HCC and 2-3% HCC patients carry mutations in NLRP12. Nlrp12-/- mice were highly susceptible to DEN or DEN plus CCl4-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. Citation Format: Hasan Zaki. NOD-like receptor NLRP12 suppresses hepatocellular carcinoma via regulation of JNK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2347.