Low NLRP3 expression predicts a better prognosis of colorectal cancer

Abstract

Background: NOD-like receptor pyrin domain-3 (NLRP3) inflammasome activation is a double-edged sword in tumorigenesis. Whether NLRP3 is involved in the progression and prognosis of colorectal cancer (CRC) remains elucidated and is the focus of this study. Methods: Immunohistochemistry (IHC) was applied on tissue microarray to determine the expression of NLRP3 in CRC patients. All 100 patients were divided into the low NLRP3 group and the high NLRP3 group according to their NLRP3 IHC scoring. Additionally, CRC xenografts were established by injecting HCT116 or RKO cells subcutaneously into nude mice. Cell proliferation and apoptosis were determined in HCT116 cells after treatment with NLRP3 inhibitor MCC950. Results: NLRP3 expression was up-regulated in colon adenocarcinoma tissues compared with that in paracancerous tissues in CRC patients, HCT116 xenograft, and RKO xenograft. High NLRP3 level correlated with the advanced TNM classification of malignant tumors, the occurrence of distant metastasis, vascular invasion, and positive lymph nodes. Furthermore, Kaplan-Meier survival analysis revealed that a high NLRP3 level was associated with a low 5-year survival rate and even a low 10-year survival rate. Moreover, the multivariable Cox proportional hazards regression model implied that NLRP3 expression level was an independent risk factor for CRC prognosis. Inhibition of NLRP3 by MCC950 suppressed cell proliferation, induced cell apoptosis, and decreased mRNA levels of interleukin 1β and interleukin 18 in HCT116 cells. Conclusions: High level of NLRP3 predicts poor survival in CRC patients. NLRP3 is a putative prognostic biomarker and a potential therapeutic target in CRC treatments.

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

“…In line with this, activation of NLRP3 by high glucose levels was demonstrated by Wang et al [138]. Shi and colleagues [139] recently showed significantly upregulated expression of NLRP3 in colon adenocarcinoma tissues as compared to adjacent normal tissue. In addition, high expression of NLRP3 was associated with poor prognosis and reduced survival of colon cancer patients [139].…”

“…Shi and colleagues [139] recently showed significantly upregulated expression of NLRP3 in colon adenocarcinoma tissues as compared to adjacent normal tissue. In addition, high expression of NLRP3 was associated with poor prognosis and reduced survival of colon cancer patients [139]. The main role of inflammasomes is the regulation of caspase-1 activity, which promotes the secretion of pro-inflammatory cytokines IL-1β and IL-18.…”

An Epigenetic Insight into NLRP3 Inflammasome Activation in Inflammation-Related Processes

“…Inflammasome dysregulation has been most often associated with tumor prognosis, although there have been some controversial results reported. While some authors have shown a clear association between high levels of inflammasome activity and poor survival, for example in colorectal cancer and laryngeal squamous cell carcinoma [ 14 , 134 ], others have proposed NLRP3 inflammasome-dependent pyroptosis induction as a therapy for cases of acute myeloid leukemia or colorectal cancer [ 135 ].…”

“…The NLRP3-inflammasome is initially generated to restore cellular homeostasis and to avoid infections or situations in which damage may occur. Nevertheless, exacerbated NLRP3 inflammasome activation is involved in the pathogenesis of many diseases such as Alzheimer’s, rheumatoid arthritis, renal diseases and tumors, all of which are characterized by significant chronic inflammation [ 12 , 13 , 14 ]. It has been associated with the ability of NLRP3 inflammasome to sense and be activated by a plethora of DAMPs, including β-amyloid plaques, cholesterol and uric acid crystals, and oxidized low-density proteins.…”

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis

“…The NLRP3 inflammasome has been implicated in promoting the progression of several malignancies by influencing the intrinsic invasiveness of the tumor while also promoting the process of epithelial-mesenchymal transition (EMT) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Indeed, NLRP3 has been shown to be overexpressed by many cancers, while elevated levels of tumor NLRP3 expression have also been associated with an inferior clinical prognosis [ 15 , 21 , 22 , 23 ]. This is consistent with data showing NLRP3 amplification across several solid tumor types, implicating NLRP3 as a potential oncogene [ 24 ].…”