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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

NLRP3 Promotes Colorectal Cancer Cell Proliferation and Metastasis via Regulating Epithelial Mesenchymal Transformation

Author(s): Xinyu Shao, Zhiyi Lei* and Chunli Zhou *

Volume 20, Issue 7, 2020

Page: [820 - 827] Pages: 8

DOI: 10.2174/1871520620666200220112741

Price: $65

Abstract

Background: Nucleotide-binding domain Leucine-rich Repeat Protein 3 (NLRP3) plays a regulatory role in the immune and inflammatory responses, and has been implicated in Colorectal Cancer (CRC) progression and metastasis. However, the underlying molecular mechanisms have not been fully elucidated.

Methods: In this study, we analyzed the expression levels of NLRP3 in human CRC tissues, and performed functional assays in CRC cell lines and a subcutaneous tumor model to elucidate its role in the development and progression of CRC.

Results: In this study, we found that NLRP3 was significantly upregulated in human CRC tissues and was associated with tumor size and invasion, lymph node metastasis, venous invasion, neural invasion and TNM staging. Furthermore, knockdown of NLRP3 in CRC cells inhibited their migration and growth in vitro and in vivo, and reversed Epithelial-Mesenchymal Transition (EMT) in vitro.

Conclusion: Our findings indicate that NLRP3 likely regulates CRC metastasis by activating the EMT program, and is a potential therapeutic target.

Keywords: Colorectal cancer, NLRP3, epithelial-mesenchymal transition, metastasis, TNM, therapeutic target.

Graphical Abstract
[1]
Siegel, R.; Desantis, C.; Jemal, A. Colorectal cancer statistics, 2014. CA Cancer J. Clin., 2014, 64(2), 104-117.
[http://dx.doi.org/10.3322/caac.21220] [PMID: 24639052]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[3]
Siegel, R.L.; Miller, K.D.; Fedewa, S.A.; Ahnen, D.J.; Meester, R.G.S.; Barzi, A.; Jemal, A. Colorectal cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(3), 177-193.
[http://dx.doi.org/10.3322/caac.21395] [PMID: 28248415]
[4]
Ng, S.C.; Wong, S.H. Colorectal cancer screening in Asia. Br. Med. Bull., 2013, 105, 29-42.
[http://dx.doi.org/10.1093/bmb/lds040] [PMID: 23299409]
[5]
Oliveira, A.F.; Bretes, L.; Furtado, I. Review of PD-1/PD-L1 inhibitors in metastatic dMMR/MSI-H colorectal cancer. Front. Oncol., 2019, 9, 396.
[http://dx.doi.org/10.3389/fonc.2019.00396] [PMID: 31139574]
[6]
Lee, D.W.; Han, S.W.; Cha, Y.; Bae, J.M.; Kim, H.P.; Lyu, J.; Han, H.; Kim, H.; Jang, H.; Bang, D.; Won, J.K.; Jeong, S.Y.; Park, K.J.; Kang, G.H.; Kim, T.Y. Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy. BMC Cancer, 2019, 19(1), 421.
[http://dx.doi.org/10.1186/s12885-019-5650-0] [PMID: 31060539]
[7]
Matos, I.; Noguerido, A.; Ros, J.; Mulet, N.; Argilés, G.; Elez, É.; Tabernero, J. Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials. Expert Opin. Investig. Drugs, 2019, 28(5), 463-471.
[http://dx.doi.org/10.1080/13543784.2019.1599860] [PMID: 30905200]
[8]
Perera, A.P.; Sajnani, K.; Dickinson, J.; Eri, R.; Körner, H. NLRP3 inflammasome in colitis and colitis-associated colorectal cancer. Mamm. Genome, 2018, 29(11-12), 817-830.
[http://dx.doi.org/10.1007/s00335-018-9783-2] [PMID: 30206651]
[9]
Liu, B.; Zhang, Y.; Fan, Y.; Wang, S.; Li, Z.; Deng, M.; Li, C.; Wang, J.; Ma, R.; Wang, X.; Wang, Y.; Xu, L.; Hou, K.; Che, X.; Liu, Y.; Qu, X. Leucine-rich Repeat Neuronal Protein-1(LRRN1)suppresses apoptosis of gastric cancer cells through regulation of Fas/FasL. Cancer Sci., 2019, 110(7), 2145-2155.
[http://dx.doi.org/10.1111/cas.14042]
[10]
Prossomariti, A.; Sokol, H.; Ricciardiello, L. Nucleotide-binding domain leucine-rich repeat containing proteins and intestinal microbiota: Pivotal players in colitis and colitis-associated cancer development. Front. Immunol., 2018, 9, 1039.
[http://dx.doi.org/10.3389/fimmu.2018.01039] [PMID: 29868004]
[11]
Wang, W.; Mao, S.; Yu, H.; Wu, H.; Shan, X.; Zhang, X.; Cui, G.; Liu, X. Pinellia pedatisecta lectin exerts a proinflammatory activity correlated with ROS-MAPKs/NF-κB pathways and the NLRP3 inflammasome in RAW264.7 cells accompanied by cell pyroptosis. Int. Immunopharmacol., 2019, 66, 1-12.
[http://dx.doi.org/10.1016/j.intimp.2018.11.002] [PMID: 30415189]
[12]
Lee, H.W.; Lee, C.G.; Rhee, D.K.; Um, S.H.; Pyo, S. Sinigrin inhibits production of inflammatory mediators by suppressing NF-κB/MAPK pathways or NLRP3 inflammasome activation in macrophages. Int. Immunopharmacol., 2017, 45, 163-173.
[http://dx.doi.org/10.1016/j.intimp.2017.01.032] [PMID: 28219839]
[13]
He, Q.; You, H.; Li, X.M.; Liu, T.H.; Wang, P.; Wang, B.E. HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 by activation of p38 MAPK and NF-κB through receptors for advanced glycation end-products in macrophages. Asian Pac. J. Cancer Prev., 2012, 13(4), 1365-1370.
[http://dx.doi.org/10.7314/APJCP.2012.13.4.1365] [PMID: 22799333]
[14]
Lazaridis, L.D.; Pistiki, A.; Giamarellos-Bourboulis, E.J.; Georgitsi, M.; Damoraki, G.; Polymeros, D.; Dimitriadis, G.D.; Triantafyllou, K. Activation of NLRP3 inflammasome in inflammatory bowel disease: Differences between Crohn’s disease and ulcerative colitis. Dig. Dis. Sci., 2017, 62(9), 2348-2356.
[http://dx.doi.org/10.1007/s10620-017-4609-8] [PMID: 28523573]
[15]
Zhang, Y.; Kong, W.; Jiang, J. Prevention and treatment of cancer targeting chronic inflammation: research progress, potential agents, clinical studies and mechanisms. Sci. China Life Sci., 2017, 60(6), 601-616.
[http://dx.doi.org/10.1007/s11427-017-9047-4] [PMID: 28639101]
[16]
Diepenbruck, M.; Christofori, G. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr. Opin. Cell Biol., 2016, 43, 7-13.
[http://dx.doi.org/10.1016/j.ceb.2016.06.002] [PMID: 27371787]
[17]
Muhammad, N.; Bhattacharya, S.; Steele, R.; Phillips, N.; Ray, R.B. Involvement of c-Fos in the promotion of cancer stem-like cell properties in head and neck squamous cell carcinoma. Clin. Cancer Res., 2017, 23(12), 3120-3128.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-2811] [PMID: 27965308]
[18]
Yao, Y.; Zhou, D.; Shi, D.; Zhang, H.; Zhan, S.; Shao, X.; Sun, K.; Sun, L.; Wu, G.; Tian, K.; Zhu, X.; He, S. GLI1 overexpression promotes gastric cancer cell proliferation and migration and induces drug resistance by combining with the AKT-mTOR pathway. Biomed. Pharmacother., 2019, 111, 993-1004.
[http://dx.doi.org/10.1016/j.biopha.2019.01.018] [PMID: 30841479]
[19]
Yao, Y.; Yang, X.; Sun, L.; Sun, S.; Huang, X.; Zhou, D.; Li, T.; Zhang, W.; Abumrad, N.A.; Zhu, X.; He, S.; Su, X. Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer. EBioMedicine, 2019, 41, 256-267.
[http://dx.doi.org/10.1016/j.ebiom.2019.01.066] [PMID: 30738828]
[20]
Wang, K.; Karin, M. Tumor-elicited inflammation and colorectal cancer. Adv. Cancer Res., 2015, 128, 173-196.
[http://dx.doi.org/10.1016/bs.acr.2015.04.014] [PMID: 26216633]
[21]
Cox, L.A.T., Jr Risk analysis implications of dose-response thresholds for NLRP3 inflammasome-mediated diseases: Respirable crystalline silica and lung cancer as an example. Dose Response, 2019, 17(2), 1559325819836900
[http://dx.doi.org/10.1177/1559325819836900] [PMID: 31168301]
[22]
Li, S.; Liang, X.; Ma, L.; Shen, L.; Li, T.; Zheng, L.; Sun, A.; Shang, W.; Chen, C.; Zhao, W.; Jia, J. MiR-22 sustains NLRP3 expression and attenuates H. pylori-induced gastric carcinogenesis. Oncogene, 2018, 37(7), 884-896.
[http://dx.doi.org/10.1038/onc.2017.381] [PMID: 29059152]
[23]
Jolly, M.K.; Ware, K.E.; Gilja, S.; Somarelli, J.A.; Levine, H. EMT and MET: necessary or permissive for metastasis? Mol. Oncol., 2017, 11(7), 755-769.
[http://dx.doi.org/10.1002/1878-0261.12083] [PMID: 28548345]
[24]
Vincent, C.T.; Fuxe, J. EMT, inflammation and metastasis. Semin. Cancer Biol., 2017, 47, 168-169.
[http://dx.doi.org/10.1016/j.semcancer.2017.09.003] [PMID: 28916486]
[25]
Allen, I.C.; TeKippe, E.M.; Woodford, R.M.; Uronis, J.M.; Holl, E.K.; Rogers, A.B.; Herfarth, H.H.; Jobin, C.; Ting, J.P. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med., 2010, 207(5), 1045-1056.
[http://dx.doi.org/10.1084/jem.20100050] [PMID: 20385749]
[26]
Clark, S.E.; Schmidt, R.L.; McDermott, D.S.; Lenz, L.L.A.A. Batf3/Nlrp3/IL-18 axis promotes natural killer cell IL-10 production during Listeria monocytogenes infection. Cell Rep., 2018, 23(9), 2582-2594.
[http://dx.doi.org/10.1016/j.celrep.2018.04.106] [PMID: 29847790]
[27]
Ketelut-Carneiro, N.; Silva, G.K.; Rocha, F.A.; Milanezi, C.M.; Cavalcanti-Neto, F.F.; Zamboni, D.S.; Silva, J.S. IL-18 triggered by the Nlrp3 inflammasome induces host innate resistance in a pulmonary model of fungal infection. J. Immunol., 2015, 194(9), 4507-4517.
[http://dx.doi.org/10.4049/jimmunol.1402321] [PMID: 25825440]

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