Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma

Authors: Cong-Fa Huang, Lei Chen, Yi-Cun Li, Lei Wu, Guang-Tao Yu, Wen-Feng Zhang, Zhi-Jun Sun

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Login to get access

Abstract

Background

NLRP3 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.

Methods

In 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.

Results

The 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.

Conclusions

Our 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.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
2.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRefPubMed
3.
Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4-5):309–16.CrossRefPubMed
4.
5.
Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27(27):229.CrossRefPubMed
6.
Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol. 2007;7(1):31–40.CrossRefPubMed
7.
Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res. 2015;8:15–27.PubMedPubMedCentral
8.
Okamoto M, Liu W, Luo Y, Tanaka A, Cai X, Norris DA, Dinarello CA, Fujita M. Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta. J Biol Chem. 2010;285(9):6477–88.CrossRefPubMed
9.
Wang Y, Kong H, Zeng X, Liu W, Wang Z, Yan X, Wang H, Xie W. Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncol Rep. 2016;35(4):2053–64.CrossRefPubMed
10.
Wang H, Wang Y, Du Q, Lu P, Fan H, Lu J, Hu R. Inflammasome-independent NLRP3 is required for epithelial-mesenchymal transition in colon cancer cells. Exp Cell Res. 2016;342(2):184–92.CrossRefPubMed
11.
Bruchard M, Mignot G, Derangere V, Chalmin F, Chevriaux A, Vegran F, Boireau W, Simon B, Ryffel B, Connat JL, et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med. 2013;19(1):57–64.CrossRefPubMed
12.
Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab Investig. 2014;94(1):52–62.CrossRefPubMed
13.
Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C, Ting JP. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 2010;207(5):1045–56.CrossRefPubMedPubMedCentral
14.
Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol. 2010;185(8):4912–20.CrossRefPubMedPubMedCentral
15.
16.
Tanno T, Matsui W. Development and maintenance of cancer stem cells under chronic inflammation. J Nippon Med Sch. 2011;3(78):138–45.CrossRef
17.
Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J. IL-1beta promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer. 2012;11(1):87.CrossRefPubMedPubMedCentral
18.
Zitvogel L, Kepp O, Galluzzi L, Kroemer G. Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol. 2012;13(4):343–51.CrossRefPubMed
19.
Cao W, Zhang ZY, Xu Q, Sun Q, Yan M, Zhang J, Zhang P, Han ZG, Chen WT. Epigenetic silencing of MAL, a putative tumor suppressor gene, can contribute to human epithelium cell carcinoma. Mol Cancer. 2010;9(1):296.CrossRefPubMedPubMedCentral
20.
Coll RC, Robertson AA, Chae JJ, Higgins SC, Munoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248–55.PubMedPubMedCentral
21.
Sun ZJ, Zhang L, Hall B, Bian Y, Gutkind JS, Kulkarni AB. Chemopreventive and chemotherapeutic actions of mTOR inhibitor in genetically defined head and neck squamous cell carcinoma mouse model. Clin Cancer Res. 2012;18(19):5304–13.CrossRefPubMedPubMedCentral
22.
Kong H, Wang Y, Zeng X, Wang Z, Wang H, Xie W. Differential expression of inflammasomes in lung cancer cell lines and tissues. Tumour Biol. 2015;36(10):7501–13.CrossRefPubMed
23.
Zhao ZL, Zhang L, Huang CF, Ma SR, Bu LL, Liu JF, Yu GT, Liu B, Gutkind JS, Kulkarni AB, et al. NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell. Sci Rep. 2016;6:24704.CrossRefPubMedPubMedCentral
24.
Wu L, Deng WW, Yu GT, Mao L, Bu LL, Ma SR, Liu B, Zhang WF, Sun ZJ. B7–H4 expression indicates poor prognosis of oral squamous cell carcinoma. Cancer Immunol Immunother. 2016;65(9):1035–45.CrossRefPubMed
25.
Deng WW, Mao L, Yu GT, Bu LL, Ma SR, Liu B, Gutkind JS, Kulkarni AB, Zhang WF, Sun ZJ. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5(11):e1239005.
26.
Sun ZJ, Yu GT, Huang CF, Bu LL, Liu JF, Ma SR, Zhang WF, Liu B, Zhang L. Hypoxia induce TFE3 expression in head and neck squamous cell carcinoma. Oncotarget. 2016;7(10):11651–63.CrossRefPubMedPubMedCentral
27.
Yu GT, Bu LL, Zhao YY, Mao L, Deng WW, Wu TF, Zhang WF, Sun ZJ. CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma. Oncoimmunology. 2016;5(6):e1151594.
28.
Sayed SI, Dwivedi RC, Katna R, Garg A, Pathak KA, Nutting CM, Rhys-Evans P, Harrington KJ, Kazi R. Implications of understanding cancer stem cell (CSC) biology in head and neck squamous cell cancer. Oral Oncol. 2011;47(4):237–43.CrossRefPubMed
29.
Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104(3):973.CrossRefPubMedPubMedCentral
30.
Arnold KM, Opdenaker LM, Flynn D, Sims-Mourtada J. Wound healing and cancer stem cells: inflammation as a driver of treatment resistance in breast cancer. Cancer Growth Metastasis. 2015;2015(8):1–13.
31.
Yu GT, Bu LL, Huang CF, Zhang WF, Chen WJ, Gutkind JS, Kulkarni AB, Sun ZJ. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget. 2015;6(39):42067–80.CrossRefPubMedPubMedCentral
32.
Bu LL, Zhao ZL, Liu JF, Ma SR, Huang CF, Liu B, Zhang WF, Sun ZJ. STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell. Oncotarget. 2015;6(39):41944–58.CrossRefPubMedPubMedCentral
33.
Ma SR, Wang WM, Huang CF, Zhang WF, Sun ZJ. Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition. Oncotarget. 2015;6(11):8807–21.CrossRefPubMedPubMedCentral
34.
Bian Y, Hall B, Sun ZJ, Molinolo A, Chen W, Gutkind JS, Waes CV, Kulkarni AB. Loss of TGF-beta signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene. 2012;31(28):3322–32.CrossRefPubMed
35.
Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6(378).
36.
37.
Sun Y, Zhu D, Wang G, Wang D, Zhou H, Liu X, Jiang M, Liao L, Zhou Z, Hu J. Pro-inflammatory cytokine IL-1beta up-regulates CXC Chemokine receptor 4 via notch and ERK signaling pathways in tongue Squamous cell carcinoma. PLoS One. 2015;10(7):e0132677.
38.
Panchanathan R, Liu H, Choubey D. Hypoxia primes human normal prostate epithelial cells and cancer cell lines for the NLRP3 and AIM2 inflammasome activation. Oncotarget. 2016;7(19):28183–94.CrossRefPubMedPubMedCentral
39.
Drexler SK, Bonsignore L, Masin M, Tardivel A, Jackstadt R, Hermeking H, Schneider P, Gross O, Tschopp J, Yazdi AS. Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc Natl Acad Sci U S A. 2012;109(45):18384–9.CrossRefPubMedPubMedCentral
40.
Ikuta T, Kobayashi Y, Kitazawa M, Shiizaki K, Itano N, Noda T, Pettersson S, Poellinger L, Fujii-Kuriyama Y, Taniguchi S, Kawajiri K. ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. Carcinogenesis. 2013;34(7):1620–7.CrossRefPubMed
41.
Huang CF, Zhang L, Ma SR, Zhao ZL, Wang WM, He KF, Zhao YF, Zhang WF, Liu B, Sun ZJ. Clinical significance of Keap1 and Nrf2 in oral Squamous cell carcinoma. PLoS One. 2013;8(12):e83479.CrossRefPubMedPubMedCentral
42.
Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, Betz KS, Penz-Oesterreicher M, Bjorkdahl O, Fox JG, Wang TC. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. 2008;14(5):408–19.CrossRefPubMedPubMedCentral
43.
Li H, Ambade A, Re F. Cutting edge: necrosis activates the NLRP3 inflammasome. J Immunol. 2009;183(3):1528–32.CrossRefPubMed
44.
Lewis AM, Varghese S, Xu H, Alexander HR. Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J Transl Med. 2006;4(1):48.CrossRefPubMedPubMedCentral
45.
Wu CS, Chang KP, OuYang CN, Kao HK, Hsueh C, Chen LC, Cheng HY, Liang Y, Liou W, Liang CL, Chang YS. ASC contributes to metastasis of oral cavity squamous cell carcinoma. Oncotarget. 2016;7(31):50074.CrossRefPubMedPubMedCentral
46.
Mohammed A, Janakiram NB, Madka V, Brewer M, Ritchie RL, Lightfoot S, Kumar G, Sadeghi M, Patlolla JM, Yamada HY, et al. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression. Oncotarget. 2015;6(17):15524–39.CrossRefPubMedPubMedCentral
47.
Lee CH, Chang JS, Syu SH, Wong TS, Chan JY, Tang YC, Yang ZP, Yang WC, Chen CT, Lu SC, et al. IL-1beta promotes malignant transformation and tumor aggressiveness in oral cancer. J Cell Physiol. 2015;230(4):875–84.CrossRefPubMed
Metadata
Title
NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma
Authors
Cong-Fa Huang
Lei Chen
Yi-Cun Li
Lei Wu
Guang-Tao Yu
Wen-Feng Zhang
Zhi-Jun Sun
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0589-y

Other articles of this Issue 1/2017

Journal of Experimental & Clinical Cancer Research 1/2017 Go to the issue

Research

RNA virus receptor Rig-I monitors gut microbiota and inhibits colitis-associated colorectal cancer

Research

ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population

Review

hrHPV E5 oncoprotein: immune evasion and related immunotherapies

Research

Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism

Research

Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy

Research

Site-specific selection reveals selective constraints and functionality of tumor somatic mtDNA mutations
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits