RIP2 promotes glioma cell growth by regulating TRAF3 and activating the NF‑κB and p38 signaling pathways

Cai,Xin; Yang,Yongchang; Xia,Wengrong; Kong,Haibo; Wang,Min; Fu,Wenliang; Long,Minhui; Hu,Yuhua; Xu,Donggang

doi:10.3892/or.2018.6397

RIP2 promotes glioma cell growth by regulating TRAF3 and activating the NF‑κB and p38 signaling pathways

Authors:
- Xin Cai
- Yongchang Yang
- Wengrong Xia
- Haibo Kong
- Min Wang
- Wenliang Fu
- Minhui Long
- Yuhua Hu
- Donggang Xu
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Affiliations: Laboratory of Genome Engineering, Beijing Institute of Basic Medical Sciences, Beijing 100850, P.R. China, Department of Clinical Laboratory, PLA Army General Hospital, Beijing 100700, P.R. China, Department of Neurosurgery, The Second Hospital Affiliated to Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
Published online on: April 23, 2018 https://doi.org/10.3892/or.2018.6397
Pages: 2915-2923

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Abstract

Receptor‑interacting protein 2 (RIP2) has recently been reported to be involved in tumor infiltration and cancer metastasis. However, the function of RIP2 in human astrocytoma remains unclear. In the present study, we showed that the expressions of RIP2 and Bcl‑xL were positively correlated with the malignant grade in 28 cases of astrocytoma of various grades and 6 cases of normal human tissues. In addition, increased activity of the NF‑κB and p38 signaling pathways in astrocytoma tissue was observed. Cytological experiments indicated that RIP2 promoted human glioblastoma cell proliferation by inducing expression of Bcl‑xL, and knockdown of endogenous RIP2 promoted cell apoptosis. Mechanistically, knockdown of RIP2 suppressed downstream events including the canonical and alternative NF‑κB pathway as well as the mitogen‑activated protein kinase (p38) pathway. In addition, the present study also demonstrated that tumor necrosis factor receptor‑associated factor 3 (TRAF3), as a novel RIP2 binding partner, was downregulated in glioma tissues and functionally was a negative regulator involved in RIP2‑induced glioma cell growth. Taken together, the present study established a negative link between RIP2 and TRAF3 proteins and identifies a new pathway for regulating astrocytoma progression.

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1	Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, et al: Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 21:2683–2710. 2007. View Article : Google Scholar : PubMed/NCBI
2	Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K and Delattre JY: Primary brain tumours in adults. Lancet. 379:1984–1996. 2012. View Article : Google Scholar : PubMed/NCBI
3	Sathornsumetee S and Rich JN: New treatment strategies for malignant gliomas. Expert Rev Anticancer Ther. 6:1087–1104. 2006. View Article : Google Scholar : PubMed/NCBI
4	Nogueira L, Ruiz-Ontañon P, Vazquez-Barquero A, Lafarga M, Berciano MT, Aldaz B, Grande L, Casafont I, Segura V, Robles EF, et al: Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo. Oncogene. 30:3537–3548. 2011. View Article : Google Scholar : PubMed/NCBI
5	Woo JS, Kim SM, Jeong CH, Ryu CH and Jeun SS: Lipoxygenase inhibitor MK886 potentiates TRAIL-induced apoptosis through CHOP- and p38 MAPK-mediated up-regulation of death receptor 5 in malignant glioma. Biochem Biophys Res Commun. 431:354–359. 2013. View Article : Google Scholar : PubMed/NCBI
6	Kim SM, Park JG, Baek WK, Suh MH, Lee H, Yoo SK, Jung KH, Suh SI and Jang BC: Cadmium specifically induces MKP-1 expression via the glutathione depletion-mediated p38 MAPK activation in C6 glioma cells. Neurosci Lett. 440:289–293. 2008. View Article : Google Scholar : PubMed/NCBI
7	Posser T, de Aguiar CB, Garcez RC, Rossi FM, Oliveira CS, Trentin AG, Neto VM and Leal RB: Exposure of C6 glioma cells to Pb(II) increases the phosphorylation of p38(MAPK) and JNK1/2 but not of ERK1/2. Arch Toxicol. 81:407–414. 2007. View Article : Google Scholar : PubMed/NCBI
8	Yoshino Y, Aoyagi M, Tamaki M, Duan L, Morimoto T and Ohno K: Activation of p38 MAPK and/or JNK contributes to increased levels of VEGF secretion in human malignant glioma cells. Int J Oncol. 29:981–987. 2006.PubMed/NCBI
9	Zhang Z, Lv J, Lei X, Li S, Zhang Y, Meng L, Xue R and Li Z: Baicalein reduces the invasion of glioma cells via reducing the activity of p38 signaling pathway. PLoS One. 9:e903182014. View Article : Google Scholar : PubMed/NCBI
10	Zhang D, Lin J and Han J: Receptor-interacting protein (RIP) kinase family. Cell Mol Immunol. 7:243–249. 2010. View Article : Google Scholar : PubMed/NCBI
11	Yin X, Krikorian P, Logan T and Csizmadia V: Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-kappaB signaling pathways and involves a novel feed-forward regulatory mechanism. Mol Cell Biochem. 333:251–259. 2010. View Article : Google Scholar : PubMed/NCBI
12	Thome M, Hofmann K, Burns K, Martinon F, Bodmer JL, Mattmann C and Tschopp J: Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Curr Biol. 8:885–888. 1998. View Article : Google Scholar : PubMed/NCBI
13	Navas TA, Baldwin DT and Stewart TA: RIP2 is a Raf1-activated mitogen-activated protein kinase kinase. J Biol Chem. 274:33684–33690. 1999. View Article : Google Scholar : PubMed/NCBI
14	Jacquet S, Nishino Y, Kumphune S, Sicard P, Clark JE, Kobayashi KS, Flavell RA, Eickhoff J, Cotten M and Marber MS: The role of RIP2 in p38 MAPK activation in the stressed heart. J Biol Chem. 283:11964–11971. 2008. View Article : Google Scholar : PubMed/NCBI
15	McCully ML, Baroja ML, Chau TA, Jain AK, Barra L, Salgado A, Blake PG and Madrenas J: Receptor-interacting protein 2 is a marker for resolution of peritoneal dialysis-associated peritonitis. Kidney Int. 72:1273–1281. 2007. View Article : Google Scholar : PubMed/NCBI
16	Hollenbach E, Vieth M, Roessner A, Neumann M, Malfertheiner P and Naumann M: Inhibition of RICK/nuclear factor-kappaB and p38 signaling attenuates the inflammatory response in a murine model of Crohn disease. J Biol Chem. 280:14981–14988. 2005. View Article : Google Scholar : PubMed/NCBI
17	Humphries F, Yang S, Wang B and Moynagh PN: RIP kinases: Key decision makers in cell death and innate immunity. Cell Death Differ. 22:225–236. 2015. View Article : Google Scholar : PubMed/NCBI
18	Goh FY, Cook KL, Upton N, Tao L, Lah LC, Leung BP and Wong WS: Receptor-interacting protein 2 gene silencing attenuates allergic airway inflammation. J Immunol. 191:2691–2699. 2013. View Article : Google Scholar : PubMed/NCBI
19	Singel SM, Batten K, Cornelius C, Jia G, Fasciani G, Barron SL, Wright WE and Shay JW: Receptor-interacting protein kinase 2 promotes triple-negative breast cancer cell migration and invasion via activation of nuclear factor-kappaB and c-Jun N-terminal kinase pathways. Breast Cancer Res. 16:R282014. View Article : Google Scholar : PubMed/NCBI
20	Zhang H and Chin AI: Role of Rip2 in development of tumor-infiltrating MDSCs and bladder cancer metastasis. PLoS One. 9:e947932014. View Article : Google Scholar : PubMed/NCBI
21	Cai X, Du J, Liu Y, Xia W, Liu J, Zou M, Wang Y, Wang M, Su H and Xu D: Identification and characterization of receptor-interacting protein 2 as a TNFR-associated factor 3 binding partner. Gene. 517:205–211. 2013. View Article : Google Scholar : PubMed/NCBI
22	Häcker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Häcker G, et al: Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature. 439:204–207. 2006. View Article : Google Scholar : PubMed/NCBI
23	Hildebrand JM, Yi Z, Buchta CM, Poovassery J, Stunz LL and Bishop GA: Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunol Rev. 244:55–74. 2011. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Allen M, Bjerke M, Edlund H, Nelander S and Westermark B: Origin of the U87MG glioma cell line: Good news and bad news. Sci Transl Med. 8:354re32016. View Article : Google Scholar : PubMed/NCBI
26	Cai X, Wang M, Kong H, Liu J, Liu Y, Xia W, Zou M, Wang J, Su H and Xu D: Prokaryotic expression, purification and functional characterization of recombinant human RIP2. Mol Biol Rep. 40:59–65. 2013. View Article : Google Scholar : PubMed/NCBI
27	Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J, Huang G, Green M, Kundu M, Chi H, et al: Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol. 14:480–488. 2013. View Article : Google Scholar : PubMed/NCBI
28	Magalhaes JG, Lee J, Geddes K, Rubino S, Philpott DJ and Girardin SE: Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur J Immunol. 41:1445–1455. 2011. View Article : Google Scholar : PubMed/NCBI
29	Tigno-Aranjuez JT, Asara JM and Abbott DW: Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses. Genes Dev. 24:2666–2677. 2010. View Article : Google Scholar : PubMed/NCBI
30	Nogueira L, Ruiz-Ontañon P, Vazquez-Barquero A, Moris F and Fernandez-Luna JL: The NFκB pathway: A therapeutic target in glioblastoma. Oncotarget. 2:646–653. 2011. View Article : Google Scholar : PubMed/NCBI
31	Tchoghandjian A, Jennewein C, Eckhardt I, Rajalingam K and Fulda S: Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells. Cell Death Dis. 4:e5642013. View Article : Google Scholar : PubMed/NCBI
32	Zhao X, Laver T, Hong SW, Twitty GB Jr, Devos A, Devos M, Benveniste EN and Nozell SE: An NF-κB p65-cIAP2 link is necessary for mediating resistance to TNF-α induced cell death in gliomas. J Neurooncol. 102:367–381. 2011. View Article : Google Scholar : PubMed/NCBI
33	Xie P, Kraus ZJ, Stunz LL and Bishop GA: Roles of TRAF molecules in B lymphocyte function. Cytokine Growth Factor Rev. 19:199–207. 2008. View Article : Google Scholar : PubMed/NCBI
34	Saha SK and Cheng G: TRAF3: A new regulator of type I interferons. Cell Cycle. 5:804–807. 2006. View Article : Google Scholar : PubMed/NCBI
35	Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W, et al: Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 12:115–130. 2007. View Article : Google Scholar : PubMed/NCBI
36	Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M, et al: Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 12:131–144. 2007. View Article : Google Scholar : PubMed/NCBI
37	Xie P, Kraus ZJ, Stunz LL, Liu Y and Bishop GA: TNF receptor-associated factor 3 is required for T cell-mediated immunity and TCR/CD28 signaling. J Immunol. 186:143–155. 2011. View Article : Google Scholar : PubMed/NCBI