Prognostic association between NLRP3 inflammasome expression level and operable pancreatic adenocarcinoma

Abstract

Background The NLRP3 inflammasome is significantly associated with tumor development and metastasis in various malignancies. However, the significance of the NLRP3 inflammasome in pancreatic adenocarcinoma has not been fully determined. Therefore, we try to evaluate the expression of the NLRP3 inflammasome in pancreatic adenocarcinoma and analyzed its prognostic significance. Methods This cohort study enrolled 98 patients with primary pancreatic adenocarcinoma who received curative surgery. The NLRP3 inflammasome expression levels in cancer tissue were determined by immunohistochemistry, and compared with that of adjacent normal tissues. The association between NLRP3 inflammasome expression levels and baseline clinicopathological characteristics were also analyzed. Moreover, the correlation between NLRP3 inflammasome expression levels and survival was analyzed by log-rank test, and the survival curve was made by the Kaplan–Meier survival analysis. Results Expression of each NLRP3 inflammasome component in cancer tissue was higher than that in the adjacent normal tissues (all P < 0.05), including NLRP3, IL-1β, ASC, and Caspase-1. All four components of the NLRP3 inflammasome were closely associated with clinical stage and lymph node status (all P < 0.05). The Kaplan–Meier log rank test showed that the high expression level of the NLRP3 inflammasome was significantly related to poor overall survival in pancreatic adenocarcinoma patients. Conclusions NLRP3 inflammasome expression was upregulated in cancer tissue and closely associated with the prognosis of operable pancreatic adenocarcinoma.

Pancreatic Ductal Adenocarcinoma Cells Regulate NLRP3 Activation to Generate a Tolerogenic Microenvironment

“…Consistently, IL1β levels were found elevated in PDAC samples ( 6 ). Notably, recent studies have reported a positive correlation between NLRP3 expression and reduced survival in patients with PDAC, reinforcing the hypothesis of an important role for NLRP3 in PDAC progression ( 13 ). In humans, 14 members of the NLRP family have been identified ( 41 ), herein we demonstrated that NLRP3 mediates the increase in IL1β production in PDAC; however, the activation of other members of the family was not investigated in this study; therefore, it cannot be excluded.…”

The Co-Localization of NLRP3 and ASC Specks Does Not Automatically Entail NLRP3 Inflammasome Functionality in PDAC Cell Lines

“…We also observed a difference in the ASC amount between cell lines, but a higher ASC amount was not associated with more ASC speck formation. A high expression of ASC protein is often used as a marker for inflammasome formation in multiple types of cancer [21,31,[43][44][45][46][47][48][49]. The ASC protein levels [13] and PYCARD gene expression [50] (Figure 5e) were increased in the PDAC tissue, but our results imply that the ASC amount alone may be a poor marker for inflammasome formation.…”

“…A high gene expression of PYCARD was detected in the PDAC primary tumors and metastases (Figure 5e) and correlated with poor survival (Figure 6d). Further, an increased ASC amount has been associated with pancreatic cancer in patient material [21]. We therefore decided to investigate whether the amount of ASC protein was connected with inflammasome assembly in the PDAC cell lines.…”

“…Thus, the tumor cells themselves orchestrate an immune-modulatory program that supports tumorigenesis [17,20]. Components of the NLRP3 inflammasome, such as NLRP3, ASC and caspase-1, along with IL-1β, were shown to be present at higher levels in PDAC tumors compared to adjacent normal tissues and were associated with the clinical stage in a recent study [21]. Furthermore, clinical data have shown that high expression of ASC in PDAC tumors correlates with a poor prognosis [20,22].…”