NLRP3 in human glioma is correlated with increased WHO
grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway

Yin,Xiao-Feng; Zhang,Qiong; Chen,Zhuo-Yu; Wang,Hai-Fang; Li,Xin; Wang,Hong-Xia; Li,Hai-Xia; Kang,Chun-Min; Chu,Shuai; Li,Kai-Fei; Li,Yao; Qiu,Yu-Rong

doi:10.3892/ijo.2018.4480

NLRP3 in human glioma is correlated with increased WHO grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway

Authors:
- Xiao-Feng Yin
- Qiong Zhang
- Zhuo-Yu Chen
- Hai-Fang Wang
- Xin Li
- Hong-Xia Wang
- Hai-Xia Li
- Chun-Min Kang
- Shuai Chu
- Kai-Fei Li
- Yao Li
- Yu-Rong Qiu
View Affiliations

Affiliations: Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: July 12, 2018 https://doi.org/10.3892/ijo.2018.4480
Pages: 973-986
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioma is the most prevalent and fatal primary tumor of the central nervous system in adults, while the development of effective therapeutic strategies in clinical practice remain a challenge. Nucleotide-binding domain leucine-rich family pyrin-containing 3 (NLRP3) has been reported to be associated with tumorigenesis and progression; however, its expression and function in human glioma remain unclear. The present study was designed to explore the biological role and potential mechanism of NLRP3 in human glioma. The results demonstrated that overexpression of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase‑1 and interleukin (IL)‑1β protein in human glioma tissues were significantly correlated with higher World Health Organization grades. The in vitro biological experiments demonstrated that NLRP3 downregulation significantly inhibited the proliferation, migration and invasion, and promoted the apoptosis of SHG44 and A172 glioma cell lines. Furthermore, western blot assays revealed that the downregulation of NLRP3 significantly reduced the expression of ASC, caspase‑1 and IL‑1β protein. Furthermore, NLRP3 knockdown caused the inhibition of epithelial-mesenchymal transition (EMT), and inhibited the phosphorylation of AKT serine/threonine kinase (AKT) and phosphorylation of phosphatase and tensin homolog (PTEN). Consistently, the upregulation of NLRP3 significantly increased the expression of ASC, caspase‑1, IL‑1β and phosphorylated-PTEN, promoted proliferation, migration, invasion and EMT, inhibited apoptosis, and activated the AKT signaling pathway. The data of the present study indicate that NLRP3 affects human glioma progression and metastasis through multiple pathways, including EMT and PTEN/AKT signaling pathway regulation, enhanced inflammasome activation, and undefined inflammasome-independent mechanisms. Understanding the biological effects of NLRP3 in human glioma and the underlying mechanisms may offer novel insights for the development of glioma clinical therapeutic strategies.

View Figures

View References

1	Wen PY and Reardon DA: Neuro-oncology in 2015: Progress in glioma diagnosis, classification and treatment. Nat Rev Neurol. 12:69–70. 2016. View Article : Google Scholar : PubMed/NCBI
2	Mao K, Lei D, Zhang H and You C: MicroRNA-485 inhibits malignant biological behaviour of glioblastoma cells by directly targeting PAK4. Int J Oncol. 51:1521–1532. 2017. View Article : Google Scholar : PubMed/NCBI
3	Omuro A and DeAngelis LM: Glioblastoma and other malignant gliomas: A clinical review. JAMA. 310:1842–1850. 2013. View Article : Google Scholar : PubMed/NCBI
4	Olar A and Sulman EP: Molecular markers in low-grade glioma-toward tumor reclassification. Semin Radiat Oncol. 25:155–163. 2015. View Article : Google Scholar : PubMed/NCBI
5	Christofides A, Kosmopoulos M and Piperi C: Pathophysiological mechanisms regulated by cytokines in gliomas. Cytokine. 71:377–384. 2015. View Article : Google Scholar
6	Strowig T, Henao-Mejia J, Elinav E and Flavell R: Inflammasomes in health and disease. Nature. 481:278–286. 2012. View Article : Google Scholar : PubMed/NCBI
7	Lamkanfi M and Dixit VM: Mechanisms and functions of inflammasomes. Cell. 157:1013–1022. 2014. View Article : Google Scholar : PubMed/NCBI
8	Haneklaus M, O'Neill LA and Coll RC: Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: Recent developments. Curr Opin Immunol. 25:40–45. 2013. View Article : Google Scholar : PubMed/NCBI
9	He Y, Hara H and Núñez G: Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 41:1012–1021. 2016. View Article : Google Scholar : PubMed/NCBI
10	Kent A and Blander JM: Nod-like receptors: Key molecular switches in the conundrum of cancer. Front Immunol. 5:1852014. View Article : Google Scholar : PubMed/NCBI
11	Terlizzi M, Casolaro V, Pinto A and Sorrentino R: Inflammasome: Cancer's friend or foe. Pharmacol Ther. 143:24–33. 2014. View Article : Google Scholar : PubMed/NCBI
12	Paugh SW, Bonten EJ, Savic D, Ramsey LB, Thierfelder WE, Gurung P, Malireddi RK, Actis M, Mayasundari A, Min J, et al: NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet. 47:607–614. 2015. View Article : Google Scholar : PubMed/NCBI
13	Schneider SL, Ross AL and Grichnik JM: Do inflammatory pathways drive melanomagenesis. Exp Dermatol. 24:86–90. 2015. View Article : Google Scholar
14	Wei Q, Guo P, Mu K, Zhang Y, Zhao W, Huai W, Qiu Y, Li T, Ma X, Liu Y, et al: Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome. Lab Invest. 95:804–816. 2015. View Article : Google Scholar : PubMed/NCBI
15	Sharma N and Jha S: NLR-regulated pathways in cancer: Opportunities and obstacles for therapeutic interventions. Cell Mol Life Sci. 73:1741–1764. 2016. View Article : Google Scholar
16	Wang W, Wang X, Chun J, Vilaysane A, Clark S, French G, Bracey NA, Trpkov K, Bonni S, Duff HJ, et al: Inflammasome-independent NLRP3 augments TGF-β signaling in kidney epithelium. J Immunol. 190:1239–1249. 2013. View Article : Google Scholar
17	Wang H, Wang Y, Du Q, Lu P, Fan H, Lu J and Hu R: Inflammasome-independent NLRP3 is required for epithelial-mesenchymal transition in colon cancer cells. Exp Cell Res. 342:184–192. 2016. View Article : Google Scholar : PubMed/NCBI
18	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
19	Kahlert UD, Nikkhah G and Maciaczyk J: Epithelial-to-mesenchymal(-like) transition as a relevant molecular event in malignant gliomas. Cancer Lett. 331:131–138. 2013. View Article : Google Scholar
20	Ling G, Ji Q, Ye W, Ma D and Wang Y: Epithelial-mesenchymal transition regulated by p38/MAPK signaling pathways participates in vasculogenic mimicry formation in SHG44 cells transfected with TGF-β cDNA loaded lentivirus in vitro and in vivo. Int J Oncol. 49:2387–2398. 2016. View Article : Google Scholar : PubMed/NCBI
21	Zhuang Y, Peng H, Mastej V and Chen W: MicroRNA regulation of endothelial junction proteins and clinical consequence: MicroRNA regulation of endothelial junction proteins and clinical consequence. Mediators Inflamm. 2016:50786272016. View Article : Google Scholar
22	Tang M, Zhao Y, Liu N, Chen E, Quan Z, Wu X and Luo C: Overexpression of HepaCAM inhibits bladder cancer cell proliferation and viability through the AKT/FoxO pathway. J Cancer Res Clin Oncol. 143:793–805. 2017. View Article : Google Scholar : PubMed/NCBI
23	Lim SY, Menzies AM and Rizos H: Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma. Cancer. 123(S11): 2118–2129. 2017. View Article : Google Scholar : PubMed/NCBI
24	Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P and Han L: Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab Invest. 94:52–62. 2014. View Article : Google Scholar
25	Kong H, Wang Y, Zeng X, Wang Z, Wang H and Xie W: Differential expression of inflammasomes in lung cancer cell lines and tissues. Tumour Biol. 36:7501–7513. 2015. View Article : Google Scholar : PubMed/NCBI
26	Li Y, Li J, Li S, Li Y, Wang X, Liu B, Fu Q and Ma S: Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicol Appl Pharmacol. 286:53–63. 2015. View Article : Google Scholar : PubMed/NCBI
27	Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C and Ting JP: The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 207:1045–1056. 2010. View Article : Google Scholar : PubMed/NCBI
28	Wang Y, Kong H, Zeng X, Liu W, Wang Z, Yan X, Wang H and Xie W: Activation of NLRP3 inflammasome enhances the proliferation and migration of A549 lung cancer cells. Oncol Rep. 35:2053–2064. 2016. View Article : Google Scholar : PubMed/NCBI
29	Munoz L, Yeung YT and Grewal T: Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells. Cancer Biol Ther. 17:355–363. 2016. View Article : Google Scholar : PubMed/NCBI
30	Fathima Hurmath K, Ramaswamy P and Nandakumar DN: IL-1β microenvironment promotes proliferation, migration, and invasion of human glioma cells. Cell Biol Int. 38:1415–1422. 2014. View Article : Google Scholar : PubMed/NCBI
31	Sun W, Depping R and Jelkmann W: Interleukin-1β promotes hypoxia-induced apoptosis of glioblastoma cells by inhibiting hypoxia-inducible factor-1 mediated adrenomedullin production. Cell Death Dis. 5:e10202014. View Article : Google Scholar
32	Tarassishin L, Lim J, Weatherly DB, Angeletti RH and Lee SC: Interleukin-1-induced changes in the glioblastoma secretome suggest its role in tumor progression. J Proteomics. 99:152–168. 2014. View Article : Google Scholar : PubMed/NCBI
33	Tarassishin L, Casper D and Lee SC: Aberrant expression of interleukin-1β and inflammasome activation in human malignant gliomas. PLoS One. 9:e1034322014. View Article : Google Scholar
34	Zheng X, Jiang F, Katakowski M, Zhang ZG, Lu QE and Chopp M: ADAM17 promotes breast cancer cell malignant phenotype through EGFR-PI3K-AKT activation. Cancer Biol Ther. 8:1045–1054. 2009. View Article : Google Scholar : PubMed/NCBI
35	Song H, Zhang Y, Liu N, Zhao S, Kong Y and Yuan L: miR-92a-3p exerts various effects in glioma and glioma stem-like cells specifically targeting CDH1/β-catenin and Notch-1/Akt signaling pathways. Int J Mol Sci. 17:E17992016. View Article : Google Scholar
36	Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E and Wang L: PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 7:33440–33450. 2016.PubMed/NCBI
37	Mueller S, Phillips J, Onar-Thomas A, Romero E, Zheng S, Wiencke JK, McBride SM, Cowdrey C, Prados MD, Weiss WA, et al: PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome. Neuro-oncol. 14:1146–1152. 2012. View Article : Google Scholar : PubMed/NCBI
38	Moon SH, Kim DK, Cha Y, Jeon I, Song J and Park KS: PI3K/Akt and Stat3 signaling regulated by PTEN control of the cancer stem cell population, proliferation and senescence in a glioblastoma cell line. Int J Oncol. 42:921–928. 2013. View Article : Google Scholar : PubMed/NCBI
39	Zhang F, Wang Y, Sun P, Wang ZQ, Wang DS, Zhang DS, Wang FH, Fu JH, Xu RH and Li YH: Fibrinogen promotes malignant biological tumor behavior involving epithelial-mesenchymal transition via the p-AKT/p-mTOR pathway in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 143:2413–2424. 2017. View Article : Google Scholar : PubMed/NCBI
40	Mizushina Y, Shirasuna K, Usui F, Karasawa T, Kawashima A, Kimura H, Kobayashi M, Komada T, Inoue Y, Mato N, et al: NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1β. J Biol Chem. 290:5065–5077. 2015. View Article : Google Scholar
41	Morris EJ, Kawamura E, Gillespie JA, Balgi A, Kannan N, Muller WJ, Roberge M and Dedhar S: Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1. Nat Commun. 8:152892017. View Article : Google Scholar : PubMed/NCBI
42	Cao YY, Yu J, Liu TT, Yang KX, Yang LY, Chen Q, Shi F, Hao JJ, Cai Y, Wang MR, et al: Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signaling. Cell Death Dis. 9:172018. View Article : Google Scholar : PubMed/NCBI
43	Saitoh M, Endo K, Furuya S, Minami M, Fukasawa A, Imamura T and Miyazawa K: STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression. Oncogene. 35:1049–1057. 2016. View Article : Google Scholar
44	Lech M, Lorenz G, Kulkarni OP, Grosser MO, Stigrot N, Darisipudi MN, Günthner R, Wintergerst MW, Anz D, Susanti HE, et al: NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling. Ann Rheum Dis. 74:2224–2235. 2015. View Article : Google Scholar
45	Xiong S, Cheng JC, Klausen C, Zhao J and Leung PC: TGF-β1 stimulates migration of type II endometrial cancer cells by downregulating PTEN via activation of SMAD and ERK1/2 signaling pathways. Oncotarget. 7:61262–61272. 2016.PubMed/NCBI
46	Eritja N, Felip I, Dosil MA, Vigezzi L, Mirantes C, Yeramian A, Navaridas R, Santacana M, Llobet-Navas D, Yoshimura A, et al: Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-beta in mouse endometrium. Cell Death Differ. 24:1443–1458. 2017. View Article : Google Scholar : PubMed/NCBI