Knockdown of TNFAIP1 inhibits growth and induces apoptosis in osteosarcoma cells through inhibition of the nuclear factor-κB pathway

Zhang,Cheng-Lin; Wang,Ce; Yan,Wang-Jun; Gao,Rui; Li,Yong-Hua; Zhou,Xu-Hui

doi:10.3892/or.2014.3291

Knockdown of TNFAIP1 inhibits growth and induces apoptosis in osteosarcoma cells through inhibition of the nuclear factor-κB pathway

Authors:
- Cheng-Lin Zhang
- Ce Wang
- Wang-Jun Yan
- Rui Gao
- Yong-Hua Li
- Xu-Hui Zhou
View Affiliations

Affiliations: Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China, Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
Published online on: June 25, 2014 https://doi.org/10.3892/or.2014.3291
Pages: 1149-1155

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

Tumor necrosis factor-α-inducible protein-1 (TNFAIP1) plays a role in DNA synthesis, DNA repair, cell apoptosis and human diseases including cancer, and may be involved in tumor progression and metastases. However, little is known concerning the function of TNFAIP1 in human osteosarcoma (OS). The aim of the present study was to investigate the function and underlying mechanisms of TNFAIP1 in human OS. The expression of TNFAIP1 was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was performed to explore the effects of lentiviral-mediated TNFAIP1 siRNA (siTNFAIP1) on cell proliferation, invasive potential and apoptosis by MTT and Transwell assays and flow cytometric analysis in OS (MG-63 and U-2 OS) cells. The results showed that the expression of TNFAIP1 protein was significantly increased in OS tissues compared with that in adjacent non-cancerous tissues (ANCTs) (73.3 vs. 48.9%, P=0.018), and was correlated with the distant metastasis of the patients with OS (P=0.029). Knockdown of TNFAIP1 suppressed cell proliferation and invasion, and induced cell apoptosis in the OS cells together with the downregulation of p65 nuclear factor-κB (NF-κB), proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2) and upregulation of caspase-3. Collectively, our findings indicate that high expression of TNFAIP1 is associated with distant metastasis of OS, and knockdown of TNFAIP1 inhibits the growth and invasion, and induces apoptosis in OS cells through inhibition of the NF-κB pathway, suggesting that TNFAIP1 may act as a potential therapeutic target for the treatment of cancer.

View Figures

View References

1	Kuijjer ML, van den Akker BE, Hilhorst R, et al: Kinome and mRNA expression profiling of high-grade osteosarcoma cell lines implies Akt signaling as possible target for therapy. BMC Med Gen. 7:42014. View Article : Google Scholar : PubMed/NCBI
2	Buddingh EP, Anninga JK, Versteegh MI, et al: Prognostic factors in pulmonary metastasized high-grade osteosarcoma. Pediatr Blood Cancer. 54:216–221. 2010.PubMed/NCBI
3	Bacci G, Longhi A, Versari M, et al: Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer. 106:1154–1161. 2006.PubMed/NCBI
4	Savage SA, Mirabello L, Wang Z, et al: Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 45:799–803. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yang L, Liu N, Hu X, et al: CK2 phosphorylates TNFAIP1 to affect its subcellular localization and interaction with PCNA. Mol Biol Rep. 37:2967–2973. 2010. View Article : Google Scholar : PubMed/NCBI
6	Link CD, Taft A, Kapulkin V, et al: Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer’s disease model. Neurobiol Aging. 24:397–413. 2003. View Article : Google Scholar : PubMed/NCBI
7	Lin MC, Lee NP, Zheng N, et al: Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus. World J Gastroenterol. 11:7564–7568. 2005.
8	Gupta J, Gaikwad AB and Tikoo K: Hepatic expression profiling shows involvement of PKC epsilon, DGK eta, Tnfalpha, and Rho kinase in type 2 diabetic nephropathy rats. J Cell Biochem. 111:944–954. 2010. View Article : Google Scholar : PubMed/NCBI
9	Grinchuk OV, Motakis E and Kuznetsov VA: Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression. BMC Genomics. 11(Suppl 1): S92010. View Article : Google Scholar
10	Kondratiev S, Duraisamy S, Unitt CL, et al: Aberrant expression of the dendritic cell marker TNFAIP2 by the malignant cells of Hodgkin lymphoma and primary mediastinal large B-cell lymphoma distinguishes these tumor types from morphologically and phenotypically similar lymphomas. Am J Surg Pathol. 35:1531–1539. 2011. View Article : Google Scholar
11	Dumon K, Rossbach C, Harms B, et al: Tumor necrosis factor-alpha (TNF-alpha) gene polymorphism in surgical intensive care patients with SIRS. Langenbecks Arch Chir Suppl Kongressbd. 115(Suppl I): 387–390. 1998.(In German).
12	Liu XW, Lu FG, Zhang GS, et al: Proteomics to display tissue repair opposing injury response to LPS-induced liver injury. World J Gastroenterol. 10:2701–2705. 2004.PubMed/NCBI
13	Sparks AB, Peterson SN, Bell C, et al: Mutation screening of the TNFRSF11A gene encoding receptor activator of NFκB (RANK) in familial and sporadic Paget’s disease of bone and osteosarcoma. Calcif Tissue Int. 68:151–155. 2001.
14	Javelaud D and Besançon F: NF-κB activation results in rapid inactivation of JNK in TNFα-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-κB. Oncogene. 20:4365–4372. 2001.
15	Chen LC, Chen CC, Liang Y, et al: A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma. Mod Pathol. 24:175–184. 2011. View Article : Google Scholar : PubMed/NCBI
16	Xu Y, Ma H, Yu H, et al: The miR-184 binding-site rs8126 T>C polymorphism in TNFAIP2 is associated with risk of gastric cancer. PLoS One. 8:e649732013.PubMed/NCBI
17	Zhu Y, Yao Z, Wu Z, et al: Role of tumor necrosis factor alpha-induced protein 1 in paclitaxel resistance. Oncogene. Aug 5–2013.(Epub ahead of print). View Article : Google Scholar
18	Zhou C, Li X, Zhang X, et al: microRNA-372 maintains oncogene characteristics by targeting TNFAIP1 and affects NFκB signaling in human gastric carcinoma cells. Int J Oncol. 42:635–642. 2013.PubMed/NCBI
19	Zhang X, Li X, Tan Z, et al: MicroRNA-373 is upregulated and targets TNFAIP1 in human gastric cancer, contributing to tumorigenesis. Oncol Lett. 6:1427–1434. 2013.PubMed/NCBI
20	Chen CC, Liu HP, Chao M, et al: NF-κB-mediated transcriptional upregulation of TNFAIP2 by the Epstein-Barr virus oncoprotein, LMP1, promotes cell motility in nasopharyngeal carcinoma. Oncogene. Aug 26–2013.(Epub ahead of print). View Article : Google Scholar
21	Cheng YH, Utsunomiya H, Pavone ME, et al: Retinoic acid inhibits endometrial cancer cell growth via multiple genomic mechanisms. J Mol Endocrinol. 46:139–153. 2011. View Article : Google Scholar : PubMed/NCBI
22	Rusiniak ME, Yu M, Ross DT, et al: Identification of B94 (TNFAIP2) as a potential retinoic acid target gene in acute promyelocytic leukemia. Cancer Res. 60:1824–1829. 2000.PubMed/NCBI
23	Kim DM, Chung KS, Choi SJ, et al: RhoB induces apoptosis via direct interaction with TNFAIP1 in HeLa cells. Int J Cancer. 125:2520–2527. 2009.PubMed/NCBI
24	Javelaud D, Poupon MF, Wietzerbin and Besançon F: Inhibition of constitutive NF-κB activity suppresses tumorigenicity of Ewing sarcoma EW7 cells. Int J Cancer. 98:193–198. 2002.
25	Hu X, Yan F, Wang F, et al: TNFAIP1 interacts with KCTD10 to promote the degradation of KCTD10 proteins and inhibit the transcriptional activities of NF-κB and AP-1. Mol Biol Rep. 39:9911–9919. 2012.PubMed/NCBI
26	Risio M: Cell proliferation in colorectal tumor progression: an immunohistochemical approach to intermediate biomarkers. J Cell Biochem (Suppl). 16G:79–87. 1992. View Article : Google Scholar : PubMed/NCBI
27	Hornebeck W, Lambert E, Petitfrère E and Bernard P: Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression. Biochimie. 87:377–383. 2005. View Article : Google Scholar : PubMed/NCBI
28	Shah SJ and Sylvester PW: γ-Tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor κB activity. Exp Biol Med. 230:235–241. 2005.
29	Philip S, Bulbule A and Kundu GC: Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-κB-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells. J Biol Chem. 276:44926–44935. 2001.
30	Moalic-Juge S, Liagre B, Duval R, et al: The anti-apoptotic property of NS-398 at high dose can be mediated in part through NF-κB activation, hsp70 induction and a decrease in caspase-3 activity in human osteosarcoma cells. Int J Oncol. 20:1255–1262. 2002.PubMed/NCBI
31	Zhou J, Hu X, Xiong X, et al: Cloning of two rat PDIP1 related genes and their interactions with proliferating cell nuclear antigen. J Exp Zool A Comp Exp Biol. 303:227–240. 2005. View Article : Google Scholar : PubMed/NCBI