Skip to main content
Log in

Differential expression of inflammasomes in lung cancer cell lines and tissues

  • Research Article
  • Published:
Tumor Biology

Abstract

As pivotal elements involved in inflammation, inflammasomes represent a group of multiprotein complexes triggering the maturation of proinflammatory cytokine interleukin (IL)-1β and IL-18. Although the importance of the inflammasomes in inflammatory diseases is well appreciated, a precise characterization of their expressions in lung cancer remains obscure. This study aimed to determine the expressions of inflammasomes in various lung cancer cell lines and tissues to understand their potential roles in lung cancer. Our findings showed that inflammasome components were markedly upregulated in lung cancer and elicited the maturation of IL-1β and IL-18. In addition, enormous variations in subtypes and levels of inflammasomes were detected in lung cancers depending on their histological type and grading, invasion ability, as well as chemoresistance. Generally, AIM2 inflammasome was overexpressed in nonsmall cell lung cancer (NSCLC), while NLRP3 inflammasome was upregulated in lung adenocarcinoma (ADC) and small cell lung cancer (SCLC). The high-metastatic or cisplatin-sensitive NSCLC cells expressed more inflammasome components and products than their counterpart low-metastatic or cisplatin-resistant NSCLC cells, respectively. In resected lung cancer tissues, high-grade ADC expressed more inflammasome components and products than low-grade ADC. Together, these findings suggest that inflammasomes may be crucial biomarkers for lung cancer as well as potential modulators of the biological behaviors of lung cancer. Further, pharmacotherapeutics targeting inflammasomes might be novel adjuvant therapy strategies for lung cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

IL:

Interleukin

NSCLC:

Nonsmall cell lung cancer

SCLC:

Small cell lung cancer

ADC:

Adenocarcinoma

SCC:

Squamous cell carcinoma

LCC:

Large cell carcinoma

NOD:

Nucleotide-binding oligomerization domain

NLR:

Nucleotide-binding oligomerization domain-like receptor

ASC:

Apoptosis-associated speck-like protein containing a Card domain

AIM2:

Absent in melanoma 2

qRT-PCR:

Quantitative real-time polymerase chain reaction

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol. 2013;33 Suppl 1:S79–84.

    Article  PubMed  Google Scholar 

  3. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.

    Article  CAS  PubMed  Google Scholar 

  4. Janowski AM, Kolb R, Zhang W, Sutterwala FS. Beneficial and detrimental roles of NLRs in carcinogenesis. Front Immunol. 2013;4:370.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157:1013–22.

    Article  CAS  PubMed  Google Scholar 

  6. Henao-Mejia J, Elinav E, Thaiss CA, Flavell RA. Inflammasomes and metabolic disease. Annu Rev Physiol. 2014;76:57–78.

    Article  CAS  PubMed  Google Scholar 

  7. Hao LY, Liu X, Franchi L. Inflammasomes in inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol. 2013;29:363–9.

    Article  CAS  PubMed  Google Scholar 

  8. Kolb R, Liu GH, Janowski AM, Sutterwala FS, Zhang W. Inflammasomes in cancer: a double-edged sword. Protein Cell. 2014;5:12–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dihlmann S, Tao S, Echterdiek F, Herpel E, Jansen L, Chang-Claude J, et al. Lack of absent in melanoma 2 (AIM2) expression in tumor cells is closely associated with poor survival in colorectal cancer patients. Int J Cancer. 2014;135:2387–96.

    Article  CAS  PubMed  Google Scholar 

  10. Kondo Y, Nagai K, Nakahata S, Saito Y, Ichikawa T, Suekane A, et al. Overexpression of the DNA sensor proteins, absent in melanoma 2 and interferon-inducible 16, contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation. Cancer Sci. 2012;103:782–90.

    Article  CAS  PubMed  Google Scholar 

  11. 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;185:4912–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okamoto M, Liu W, Luo Y, Tanaka A, Cai X, Norris DA, et al. Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta. J Biol Chem. 2010;285:6477–88.

    Article  CAS  PubMed  Google Scholar 

  13. Rastrick J, Birrell M. The role of the inflammasome in fibrotic respiratory diseases. Minerva Med. 2014;105:9–23.

    CAS  PubMed  Google Scholar 

  14. Chaput C, Sander LE, Suttorp N, Opitz B. NOD-like receptors in lung diseases. Front Immunol. 2013;4:393.

    Article  PubMed  PubMed Central  Google Scholar 

  15. De Nardo D, De Nardo CM, Latz E. New insights into mechanisms controlling the NLRP3 inflammasome and its role in lung disease. Am J Pathol. 2014;184:42–54.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.

    Google Scholar 

  17. Beasley MB, Brambilla E, Travis WD. The 2004 World Health Organization classification of lung tumors. Semin Roentgenol. 2005;40:90–7.

    Article  PubMed  Google Scholar 

  18. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–85.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wu Q, Qian YM, Zhao XL, Wang SM, Feng XJ, Chen XF, et al. Expression and prognostic significance of centromere protein A in human lung adenocarcinoma. Lung Cancer. 2012;77:407–14.

    Article  PubMed  Google Scholar 

  20. Wu W, Li M, Liu L, Gao J, Kong H, Ding J, et al. Astrocyte activation but not neuronal impairment occurs in the hippocampus of mice after 2 weeks of d-galactose exposure. Life Sci. 2011;89:355–63.

    Article  CAS  PubMed  Google Scholar 

  21. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, et al. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem. 2007;55:443–52.

    Article  CAS  PubMed  Google Scholar 

  22. Wehner S, Buchholz BM, Schuchtrup S, Rocke A, Schaefer N, Lysson M, et al. Mechanical strain and TLR4 synergistically induce cell-specific inflammatory gene expression in intestinal smooth muscle cells and peritoneal macrophages. Am J Physiol Gastrointest Liver Physiol. 2010;299:G1187–97.

    Article  CAS  PubMed  Google Scholar 

  23. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ghonime MG, Shamaa OR, Das S, Eldomany RA, Fernandes-Alnemri T, Alnemri ES, et al. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol. 2014;192:3881–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pontillo A, Paoluzzi E, Crovella S. The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency. Eur J Hum Genet. 2010;18:844–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sanz C, Calasanz MJ, Andreu E, Richard C, Prosper F, Fernandez-Luna JL. NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells. Biochem J. 2004;384:281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13:397–411.

    Article  CAS  PubMed  Google Scholar 

  28. Pontillo A, Girardelli M, Kamada AJ, Pancotto JA, Donadi EA, Crovella S, et al. Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity. 2012;45:271–8.

    Article  CAS  PubMed  Google Scholar 

  29. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.

    Article  CAS  PubMed  Google Scholar 

  30. Hansen KD, Timp W, Bravo HC, Sabunciyan S, Langmead B, McDonald OG, et al. Increased methylation variation in epigenetic domains across cancer types. Nat Genet. 2011;43:768–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang J, Lu K, Xiang Y, Islam M, Kotian S, Kais Z, et al. Weighted frequent gene co-expression network mining to identify genes involved in genome stability. PLoS Comput Biol. 2012;8:e1002656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Di Virgilio F. The therapeutic potential of modifying inflammasomes and NOD-like receptors. Pharmacol Rev. 2013;65:872–905.

    Article  PubMed  Google Scholar 

  34. Saxena M, Yeretssian G. NOD-like receptors: master regulators of inflammation and cancer. Front Immunol. 2014;5:327.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Alfonso-Loeches S, Urena-Peralta JR, Morillo-Bargues MJ, Oliver-De La Cruz J, Guerri C. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci. 2014;8:216.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61:1659–65.

    CAS  PubMed  Google Scholar 

  37. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2009;106:20388–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24:766–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 2012;30:677–706.

    Article  CAS  PubMed  Google Scholar 

  41. Chow MT, Sceneay J, Paget C, Wong CS, Duret H, Tschopp J, et al. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 2012;72:5721–32.

    Article  CAS  PubMed  Google Scholar 

  42. Drexler SK, Bonsignore L, Masin M, Tardivel A, Jackstadt R, Hermeking H, et al. Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc Natl Acad Sci U S A. 2012;109:18384–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ikuta T, Kobayashi Y, Kitazawa M, Shiizaki K, Itano N, Noda T, et al. ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. Carcinogenesis. 2013;34:1620–7.

    Article  CAS  PubMed  Google Scholar 

  44. Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M, et al. Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour-host interactions. Eur J Cancer. 2006;42:751–9.

    Article  CAS  PubMed  Google Scholar 

  45. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L. IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J. 2003;17:2115–7.

    CAS  PubMed  Google Scholar 

  46. Park CC, Morel JC, Amin MA, Connors MA, Harlow LA, Koch AE. Evidence of IL-18 as a novel angiogenic mediator. J Immunol. 2001;167:1644–53.

    Article  CAS  PubMed  Google Scholar 

  47. Kang JS, Bae SY, Kim HR, Kim YS, Kim DJ, Cho BJ, et al. Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44. Carcinogenesis. 2009;30:1987–96.

    Article  CAS  PubMed  Google Scholar 

  48. Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res. 2000;60:4894–906.

    CAS  PubMed  Google Scholar 

  49. McDoniels-Silvers AL, Nimri CF, Stoner GD, Lubet RA, You M. Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas. Clin Cancer Res. 2002;8:1127–38.

    CAS  PubMed  Google Scholar 

  50. Zhang W, Zhang Q, Zhang M, Zhang Y, Li F, Lei P. Analysis for the mechanism between the small cell lung cancer and non-small cell lung cancer combing the miRNA and mRNA expression profiles. Thoracic Cancer. 2015;6:70–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Clinical Lung Cancer Genome Project, Network Genomic Medicine. A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5:209ra153.

    Google Scholar 

  52. Xu Y, Li H, Chen W, Yao X, Xing Y, Wang X, et al. Mycoplasma hyorhinis activates the NLRP3 inflammasome and promotes migration and invasion of gastric cancer cells. PLoS One. 2013;8, e77955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ahmad I, Muneer KM, Tamimi IA, Chang ME, Ata MO, Yusuf N. Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome. Toxicol Appl Pharmacol. 2013;270:70–6.

    Article  CAS  PubMed  Google Scholar 

  54. Matanic D, Beg-Zec Z, Stojanovic D, Matakoric N, Flego V, Milevoj-Ribic F. Cytokines in patients with lung cancer. Scand J Immunol. 2003;57:173–8.

    Article  CAS  PubMed  Google Scholar 

  55. Watari K, Shibata T, Kawahara A, Sata K, Nabeshima H, Shinoda A, et al. Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages. PLoS One. 2014;9:e99568.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yano S, Nokihara H, Yamamoto A, Goto H, Ogawa H, Kanematsu T, et al. Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules. Cancer Sci. 2003;94:244–52.

    Article  CAS  PubMed  Google Scholar 

  57. Henao-Mejia J, Elinav E, Strowig T, Flavell RA. Inflammasomes: far beyond inflammation. Nat Immunol. 2012;13:321–4.

    Article  CAS  PubMed  Google Scholar 

  58. Sagulenko V, Thygesen SJ, Sester DP, Idris A, Cridland JA, Vajjhala PR, et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 2013;20:1149–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15:e493–503.

    Article  PubMed  Google Scholar 

  60. Drexler SK, Yazdi AS. Complex roles of inflammasomes in carcinogenesis. Cancer J. 2013;19:468–72.

    Article  CAS  PubMed  Google Scholar 

  61. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009;15:1170–8.

    Article  CAS  PubMed  Google Scholar 

  62. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, et al. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol. 2010;22:113–24.

    Article  PubMed  Google Scholar 

  63. Yanagawa N, Shiono S, Abiko M, Ogata SY, Sato T, Tamura G. New IASLC/ATS/ERS classification and invasive tumor size are predictive of disease recurrence in stage I lung adenocarcinoma. J Thorac Oncol. 2013;8:612–8.

    Article  PubMed  Google Scholar 

  64. Woo T, Okudela K, Mitsui H, Tajiri M, Yamamoto T, Rino Y, et al. Prognostic value of the IASLC/ATS/ERS classification of lung adenocarcinoma in stage I disease of Japanese cases. Pathol Int. 2012;62:785–91.

    Article  CAS  PubMed  Google Scholar 

  65. Gu J, Lu C, Guo J, Chen L, Chu Y, Ji Y, et al. Prognostic significance of the IASLC/ATS/ERS classification in Chinese patients—a single institution retrospective study of 292 lung adenocarcinoma. J Surg Oncol. 2013;107:474–80.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Professor Ming Li (University of Nebraska, Lincoln, NE) for improving the English of the manuscript. This study was supported by the National Natural Science Foundation of China (Nos. 81001427, 81273571), National Technological Special Project for “Significant New Drugs Development” (2011ZX09302-003-02), Jiangsu Province Special Program of Medical Science (BL2012012), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Hong Wang or Weiping Xie.

Additional information

Hui Kong and Yanli Wang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kong, H., Wang, Y., Zeng, X. et al. Differential expression of inflammasomes in lung cancer cell lines and tissues. Tumor Biol. 36, 7501–7513 (2015). https://doi.org/10.1007/s13277-015-3473-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3473-4

Keywords

Navigation