TIPE2 suppresses the tumorigenesis, growth and metastasis of breast cancer via inhibition of the AKT and p38 signaling pathways

Zhang,Zhenhua; Liu,Li; Liu,Chunliang; Cao,Shousong; Zhu,Yizhun; Mei,Qibing

doi:10.3892/or.2016.5192

TIPE2 suppresses the tumorigenesis, growth and metastasis of breast cancer via inhibition of the AKT and p38 signaling pathways

Authors:
- Zhenhua Zhang
- Li Liu
- Chunliang Liu
- Shousong Cao
- Yizhun Zhu
- Qibing Mei
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Affiliations: State Institute of Pharmaceutical Industry, Shanghai 201203, P.R. China, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, P.R. China, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China
Published online on: October 21, 2016 https://doi.org/10.3892/or.2016.5192
Pages: 3311-3316

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Abstract

Breast cancer is the second leading cause of cancer‑related deaths in female patients, and the main reasons are late diagnosis, limited therapeutic options and metastasis. Therefore, development of molecular therapeutic targets for breast cancer to suppress tumorigenesis, growth and metastasis may improve the therapeutic options and be of great benefit to patients. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a novel molecule for maintaining immune homeostasis and is involved in cancer development. Previous studies have shown that TIPE2 plays a suppressive role in the development of several types of human cancers. However, its role in breast cancer is still not clear. In the present study, we detected TIPE2 expression in human breast cancer and adjacent normal tissues. The expression of TIPE2 was reduced in breast cancer tissues compared to the level in adjacent normal tissues. We then established a breast cancer cell line stably expressing TIPE2 to investigate the role of TIPE2 in breast cancer carcinogenesis. Our results showed that overexpression of TIPE2 significantly inhibited the proliferation of MDA-MB‑231 cells as detected by Cell Counting Kit-8 assay and suppressed the migration and invasion of breast cancer cells as detected by Transwell migration and invasion assays in vitro. TIPE2 also promoted cell apoptosis as detected by flow cytometry analysis. Moreover, TIPE2 inhibited the tumorigenesis of breast cancer in vivo. Mechanistically, TIPE2 inhibited the phosphorylation of AKT and p38 as detected by western blot analysis. Taken together, TIPE2 suppressed breast cancer tumorigenesis, growth and metastasis possibly via regulation of the AKT and p38 signaling pathways. The results indicate that TIPE2 may be a potential therapeutic target for breast cancer therapy.

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1	DeSantis C, Ma J, Bryan L and Jemal A: Breast cancer statistics, 2013. CA Cancer J Clin. 64:52–62. 2014. View Article : Google Scholar : PubMed/NCBI
2	Bissell MJ and Hines WC: Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 17:320–329. 2011. View Article : Google Scholar : PubMed/NCBI
3	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
4	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013. View Article : Google Scholar : PubMed/NCBI
5	Filipova A, Seifrtova M, Mokry J, Dvorak J, Rezacova M, Filip S and Diaz-Garcia D: Breast cancer and cancer stem cells: A mini-review. Tumori. 100:363–369. 2014.PubMed/NCBI
6	Edge SB: Quality measurement in breast cancer. J Surg Oncol. 110:509–517. 2014. View Article : Google Scholar : PubMed/NCBI
7	Lou Y and Liu S: The TIPE (TNFAIP8) family in inflammation, immunity, and cancer. Mol Immunol. 49:4–7. 2011. View Article : Google Scholar : PubMed/NCBI
8	Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, et al: TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell. 133:415–426. 2008. View Article : Google Scholar : PubMed/NCBI
9	Freundt EC, Bidere N and Lenardo MJ: A different TIPE of immune homeostasis. Cell. 133:401–402. 2008. View Article : Google Scholar : PubMed/NCBI
10	Li D, Song L, Fan Y, Li X, Li Y, Chen J, Zhu F, Guo C, Shi Y and Zhang L: Down-regulation of TIPE2 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Clin Immunol. 133:422–427. 2009. View Article : Google Scholar : PubMed/NCBI
11	Wang LY, Fan YC, Zhao J, Gao S, Sun FK, Han J, Yang Y and Wang K: Elevated expression of tumour necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 mRNA in peripheral blood mononuclear cells is associated with disease progression of acute-on-chronic hepatitis B liver failure. J Viral Hepat. 21:64–73. 2014. View Article : Google Scholar : PubMed/NCBI
12	Lou Y, Zhang G, Geng M, Zhang W, Cui J and Liu S: TIPE2 negatively regulates inflammation by switching arginine metabolism from nitric oxide synthase to arginase. PLoS One. 9:e965082014. View Article : Google Scholar : PubMed/NCBI
13	Cui J, Zhang G, Hao C, Wang Y, Lou Y, Zhang W, Wang J and Liu S: The expression of TIPE1 in murine tissues and human cell lines. Mol Immunol. 48:1548–1555. 2011. View Article : Google Scholar : PubMed/NCBI
14	Dong QZ, Zhao Y, Liu Y, Wang Y, Zhang PX, Jiang GY, Dong XJ, Cui QZ and Wang EH: Overexpression of SCC-S2 correlates with lymph node metastasis and poor prognosis in patients with non-small-cell lung cancer. Cancer Sci. 101:1562–1569. 2010. View Article : Google Scholar : PubMed/NCBI
15	Kumar D, Gokhale P, Broustas C, Chakravarty D, Ahmad I and Kasid U: Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene. 23:612–616. 2004. View Article : Google Scholar : PubMed/NCBI
16	Gus-Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S, Zhang L and Chen YH: The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell. 45:610–618. 2012. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Li X, Liu G, Sun R, Wang L, Wang J and Wang H: Down-regulated TIPE2 is associated with poor prognosis and promotes cell proliferation in non-small cell lung cancer. Biochem Biophys Res Commun. 457:43–49. 2015. View Article : Google Scholar : PubMed/NCBI
18	Zhao Q, Zhao M, Dong T, Zhou C, Peng Y, Zhou X, Fan B, Ma W, Han M and Liu S: Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) upregulates p27 to decrease gastic cancer cell proliferation. J Cell Biochem. 116:1121–1129. 2015. View Article : Google Scholar : PubMed/NCBI
19	Zhang G, Hao C, Lou Y, Xi W, Wang X, Wang Y, Qu Z, Guo C, Chen Y and Zhang Y: Tissue-specific expression of TIPE2 provides insights into its function. Mol Immunol. 47:2435–2442. 2010. View Article : Google Scholar : PubMed/NCBI
20	Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D and Naldini L: A third-generation lentivirus vector with a conditional packaging system. J Virol. 72:8463–8471. 1998.PubMed/NCBI
21	Wu J, Zhang H, Xu C, Xu H, Zhou X, Xie Y and Tao M: TIPE2 functions as a metastasis suppressor via negatively regulating β-catenin through activating GSK3β in gastric cancer. Int J Oncol. 48:199–206. 2016.PubMed/NCBI
22	Cao X, Zhang L, Shi Y, Sun Y, Dai S, Guo C, Zhu F, Wang Q, Wang J, Wang X, et al: Human tumor necrosis factor (TNF)- alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol Cancer. 12:1492013. View Article : Google Scholar : PubMed/NCBI
23	Lauring J, Park BH and Wolff AC: The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J Natl Compr Canc Netw. 11:670–678. 2013.PubMed/NCBI
24	Yang SX, Polley E and Lipkowitz S: New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat Rev. 45:87–96. 2016. View Article : Google Scholar : PubMed/NCBI
25	Chen L, Mayer JA, Krisko TI, Speers CW, Wang T, Hilsenbeck SG and Brown PH: Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells. Cancer Res. 69:8853–8861. 2009. View Article : Google Scholar : PubMed/NCBI
26	Kim MS, Lee EJ, Kim HR and Moon A: p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res. 63:5454–5461. 2003.PubMed/NCBI
27	Liu C, Wang S, Zhu S, Wang H, Gu J, Gui Z, Jing J, Hou X and Shao Y: MAP3K1-targeting therapeutic artificial miRNA suppresses the growth and invasion of breast cancer in vivo and in vitro. Springerplus. 5:112016. View Article : Google Scholar : PubMed/NCBI