NLRP3 promotes tumor growth and metastasis in human oral squamous cell carcinoma

Abstract

BackgroundInflammasomes are reported to be abnormally expressed and activated in several malignancies and play important roles in tumor development. The present study was designed to investigate the expression and function of the NLR family pyrin domain containing protein 3 (NLRP3) inflammasome in oral squamous cell carcinoma (OSCC).MethodsNLRP3 expression in OSCC cell lines and the normal human immortalized oral epithelial cells (HIOEC) was determined by real-time PCR and western blot. Immunohistochemistry was used to examine the expression of NLRP3 and IL-1β in the paraffin-embedded OSCC tissues. The proliferation of OSCC cells was detected by the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and cell colony formation ability of the OSCC cells was also evaluated. Tumor cell migration or invasion was measured by the transwell assay and related protein markers were determined by western blot. A mouse xenograft model was established to investigate the OSCC tumor growth in vivo.ResultsSignificant higher expression of NLRP3 was observed in the OSCC cells. Obvious expression of NLRP3 and IL-1β was found in the paraffin-embedded OSCC tissues, and the NLRP3 expression levels were correlated with the tumor size, lymphonode metastatic status and IL-1β expression. Downregulating NLRP3 expression markedly reduced the cleavage of caspase-1 and production of IL-1β in OSCC cells. NLRP3 knockdown also inhibited the proliferation, migration and invasion of OSCC cells. Further investigation indicated that expressions of E-cadherin and vimentin in OSCC cells were increased, while N-cadherin expression was decreased after NLRP3 knockdown. Downregulating NLRP3 expression in OSCC cells significantly reduced the tumor growth in vivo.ConclusionsOur data suggested that the increased expression of NLRP3 in OSCC was associated with tumor growth and metastasis. NLRP3 may be considered as a potential target for OSCC therapy.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4403-9) contains supplementary material, which is available to authorized users.

Diverging inflammasome signals in tumorigenesis and potential targeting

“…IL-1β and IL-18 have been reported to induce epithelialmesenchymal transition [G] (EMT) in multiple cell types 68 . IL-1β downregulates Ecadherin expression and upregulates Snail expression in SCC 69,70 and gastric cancer cells 71 . Tumor invasion also involves degradation of the extracellular matrix by matrix metalloproteinases 72 [G].…”

Globular Adiponectin Inhibits Breast Cancer Cell Growth through Modulation of Inflammasome Activation: Critical Role of Sestrin2 and AMPK Signaling

“…Inflammasomes, cytosolic multiprotein oligomers containing a member of the NOD-like receptor protein (NLRP) family, the apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1, are responsible for producing active interleukin family cytokines in response to infection and cellular stress [17]. In addition to the crucial roles in inflammatory and immune responses, emerging evidence has indicated that inflammasomes components are markedly upregulated in various cancers, such as lung, melanoma, oral squamous cell carcinoma, and breast cancer cells [18][19][20][21][22]. In addition, activation of the inflammasome facilitates tumor progression [23,24], suggesting that inflammasomes act as mediators that bridge chronic inflammation and tumorigenesis.…”

NLRP3 inflammasome activation involved in LPS and coal tar pitch extract‐induced malignant transformation of human bronchial epithelial cells

“…Inflammation affects all stages of tumorigenesis and the key signaling pathway triggering inflammation is to activate inflammasome, which lead to inflammatory responses . NLRP3 inflammasome, a protein complex composed of NLRP3, ASC, and caspase‐1, contributes to its biological function in the pathogenesis of cancers, such as oral squamous cell carcinoma, lymphoma, and pancreatic carcinomas . However, its specific role in inflammation‐related lung carcinogenesis has not yet been explored.…”

“…According to report by National Cancer Institute in 2018, lung cancer is the leading cause of cancer‐related morbidity and mortality in China. In recent years, the theory of “inflammation and cancer” has gradually attracted people's attention, and the inflammatory microenvironment has been regarded as “seventh hallmark of cancer.” Since lung is an organ that communicates directly with the outside world, it is easily exposed to environmental pollutants and pathogenic microorganisms to form inflammatory microenvironment . Although studies have confirmed that the sustained existence of chronic inflammation in the lung is a major driving force for the development of lung cancer, the molecular mechanism that chronic inflammation promotes lung cancer has not yet been elucidated.…”

“…Subsequently, cytokines pro‐IL‐1β is converted into mature and biologically active IL‐1β, initiating inflammatory events . Growing evidences indicate that NLRP3 inflammasome is involved in the development of oral cancer, colorectal cancer and other malignant tumors, but its potential contribution to lung cancer has not yet been elucidated. In this study, we hypothesize that NLRP3 inflammasome activation may play an important role in inflammation‐related lung carcinogenesis.…”