Abstract
BackgroundNLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response. However, the roles of NLRP3 inflammasome in the tumorigenesis and development of cancer stem cells (CSCs) of squamous cell carcinoma of the head and neck (SCCHN) remain ambiguous.MethodsIn our study, tissue microarrays, ELISA, sphere-forming assay, colony formation assay and Western blot analysis were performed to evaluate the effect of NLRP3 inflammasome on the development of CSCs in human SCCHN tissue specimen, cell lines, and transgenic mouse SCCHN model.ResultsThe components of NLRP3 inflammasome, namely, NLRP3, ASC, Caspase-1, and IL-18 were correlated with CSCs markers BMI1, ALDH1 and CD44 in human SCCHN specimens. Moreover, NLRP3, Caspase-1, IL-1β, and IL-18 were highly expressed in SCCHN cell lines. NLRP3 inflammasome activated by LPS and ATP promoted sphere-forming and colony formation capacities along with an upregulation of BMI1, ALDH1 and CD44. In addition, NLRP3 inflammasome blockade by NLRP3 inhibitor MCC950 reduced sphere and colony number, also decreased the expression of BMI1, ALDH1 and CD44 in SCCHN cell lines. Expression of NLRP3, ASC, Caspase-1, IL-1β, IL-18, BMI1, ALDH1 and CD44 was upregulated in Tgfbr1/Pten 2cKO mouse SCCHN model, and NLRP3 inflammasome expression was closely related to those CSCs makers in mice SCCHN. However, MCC950 treatment reduced the expression of NLRP3 inflammasome, CSCs markers BMI1, ALDH1 and CD44 in Tgfbr1/Pten 2cKO mice SCCHN. In addition, blockade of NLRP3 inflammasome can also delayed the tumor-burdened speed in SCCHN mice.ConclusionsOur study demonstrates that NLRP3 inflammasome was upregulated and associated with the carcinogenesis and CSCs self-renewal activation in SCCHN. NLRP3 inflammasome can be a potential target in the development of novel approaches for head and neck squamous cell carcinoma therapy.
Highlights
NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response
Increased NLRP3 inflammasome was associated with cancer stem cells (CSCs) markers in human SCCHN specimen To determine whether NLRP3 inflamasome was associated with human HNSCC, we examined their expression by immunohistochemistry and found that NLRP3, Caspase-1, associated specklike protein (ASC), IL-18 were highly expressed in the cytoplasm of cancer cells, and the expression of them was negative or low in the normal mucosa (Fig. 1a)
Our results showed that the protein expression of ALDH1 was positively stained in the cytoplasm, whereas BMI1 was in the cytoplasm and nucleus in SCCHN (Fig. 1a); CD44 was mainly expressed in the membrane of cancer cells and in the basal layer of normal mucosa (Fig. 1a)
Summary
NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response. The roles of NLRP3 inflammasome in the tumorigenesis and development of cancer stem cells (CSCs) of squamous cell carcinoma of the head and neck (SCCHN) remain ambiguous. Squamous cell carcinoma of head and neck (SCCHN) is one of the major causes of mortality and ranks as the sixth most frequent human cancer globally [1]. Excessive alcohol consumption, and betel quid and derivative consumption are the major risk factors for SCCHN development. Chronic inflammation is associated with DNA and tissue damage, which includes genetic and epigenetic changes leading to cancer, such as SCCHN. Inflammasome, an intracellular multiprotein complex, switches on the inflammatory response of tissues to various stimuli, including microbe-derived
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