Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide, and it is always the consequence of chronic hepatitis and liver cirrhosis. The nucleotide-binding domain, leucine-rich family (NLR), pyrin-containing 3 (NLRP3) inflammasome has been shown to orchestrate multiple innate and adaptive immune responses. However, little is known about its role in cancer. This study was performed to investigate the role of the NLRP3 inflammasome in the development and progression of HCC. The expression of NLRP3 inflammasome components was analyzed in HCC tissues and corresponding non-cancerous liver tissues at both the mRNA and protein levels. Our data demonstrate that the expression of all of the NLRP3 inflammasome components was either completely lost or significantly downregulated in human HCC, and that the deficiency correlated significantly with advanced stages and poor pathological differentiation. In addition, our data provide an overview of the expression of NLRP3 inflammasome components in the multi-stage development of HCC and indicate a surprising link between deregulation of the NLRP3 inflammasome molecular platform and HCC progression. In conclusion, this study presents a dynamic expression pattern of NLRP3 inflammasome components in multi-stage hepatocarcinogenesis and demonstrates that deregulated expression of the inflammasome is involved in HCC progression.

Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

“…7 The primary antibodies included rabbit monoclonal anti-human ASC (#ADI-905-173, Enzo Life Sciences, San Diego, CA), IL-1β (#ab2105, Abcam, Cambridge, MA), caspase 1 (#AP6703c Abgent, Shanghai, China), ERβ (#bs-0116R, Biosynthesis Biotechnology, Beijing, China), and mouse monoclonal antihuman NLRP3 (#ab17267, Abcam). TMA slides were incubated with primary antibodies at 4°C overnight, and then washed with PBS for three times.…”

“…7 On the basis of the same expression tendency of ERβ, we believed that ERβ expression may also be correlated with the expression levels of NLRP3 inflammasome components. Statistical analysis of the IHC scores indeed defined positive correlations between the expression level of ERβ and that of NLRP3 inflammasome components, including NLRP3, ASC, caspase 1, and IL-1β (Po0.001, Table 4).…”

“…Our previous work demonstrated that expression of NLRP3 inflammasome components was significantly downregulated in HCC tissue compared with that in the adjacent non-cancerous tissue, and that the deregulation of the NLRP3 inflammasome was involved in HCC progression. 7 On the basis of the involvement of E2 in hepatocarcinogenesis 5,8,9 and its newly defined role in regulation of some NLRP3 inflammasome components, 10 we speculated that E2 might be responsible for the deregulation of NLRP3 inflammasome in HCC progression and thus contribute, to a certain degree, to the gender disparity in HCC.…”

Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies

“…A protective role for NLRP3 has been described in hepatocellular carcinoma (Wei et al, 2014); NLRP3 and caspase-1 null mice are more susceptible to azoxymethane/dextran sulfate sodiuminduced carcinogenesis (Allen et al, 2010;Zaki et al, 2010). Based on this evidence, the discovery of NLRC4 as a downstream transcriptional target of p53 constituted promising evidence for the anti-tumorigenic functions of NLR (Sadasivam et al, 2005).…”

Colorectal Cancer and NLRP-Current Knowledge

“…Different stimuli activate different inflammasomes and mediate many important processes in CLC [3,6]. NLRP1-β, NLRP3, and NLRP6's activation of caspase-1 results in maturation of proinflammatory cytokine interleukin (IL)-1β and IL-18 and pyroptosis [1,7].…”